Antisperm antibodies in the polyglandular autoimmune (PGA) syndrome type I: response to cyclical steroid therapy

OBJECTIVE: To determine if cyclical intermediate dose steroid therapy could improve semen parameters in an infertile man with sperm autoimmunity associated with the polyglandular autoimmune (PGA) syndrome. DESIGN: Sperm agglutination studies performed before, during and after three courses of cyclical intermediate dose prednisolone therapy. PATIENT: A twenty-six-year old man with polyglandular autoimmune syndrome, consisting of Addison's disease, hypoparathyroidism, chronic mucocutaneous candidiasis and alopecia totalis, presented with infertility. He had normal endocrine testicular function but severe exocrine failure evidenced by a low sperm count (4.5 x 10(6)/ml), zero motility and universal sperm agglutination. MEASUREMENTS: Sperm agglutination tests. RESULTS: At presentation the gelatin agglutination test (GAT) was strongly positive in serum (1/1204) and seminal plasma (1/64) as was the tray agglutination test (TAT) (1/32). The patient's wife had a regular menstrual cycle with normal luteal phase progesterone levels. Following three courses of cyclical prednisolone (20 mg twice daily on days 1-10 of wife's cycle, and 5 mg on days 11 and 12), sperm quantity and motility improved considerably (12 x 10(6)/ml, 40% respectively) and sperm agglutination tests became negative. After a fourth course of therapy the patient's wife became pregnant. Three months post-treatment sperm motility was very low again and agglutinating activity in serum and seminal plasma increased. CONCLUSIONS: This is the first case of male infertility due to sperm autoimmunity in association with the PGA syndrome type 1. The immunosuppressive action of cyclical intermediate dose steroid therapy led to a significant quantitative and qualitative improvement in semen parameters.     

Fas and Bcl-2 protein expression in thyrocytes of patients with nodular goiter

OBJECTIVE: The relative expression of the apoptotic protein Fas and the anti-apoptotic protein Bcl-2 were investigated in thyrocytes from patients with non-toxic nodular goiter (NTG, n=20) and Hashimoto's thyroiditis (HT, n=5), who underwent fine-needle aspiration biopsy for diagnostic reasons. On the basis of the clinical and cytological findings, the patients with NTG were sub-classified into the group of those with colloid nodules (n=9), degenerative nodules (n=6) and adenomatous nodules (n=5). METHODS: Fine-needle biopsy aspirates were examined by immunocytochemistry for Fas and Bcl-2 expression, using specific monoclonal antibodies. For the evaluation of Fas and Bcl-2 immuno-reactivity, an expression index, based on the number of cells with positive staining, was used: grade 1 included samples with positive staining in <20% of cells; grade 2 included samples with 20-50% positive cells; and grade 3 included samples with >50% positive cells. RESULTS: Fas protein expression was generally low (grade 1) in patients with nodular goiter, in contrast to patients with HT, in whom high expression was detected (grade 3). Only in aspirates from degenerative nodules (four out of six), and in which lymphocytes were also present, was Fas expressed at an intermediate level (grade 2). On the other hand, Bcl-2 protein was differentially expressed among the nodule subtypes. It was low in colloid and degenerative nodules (grade 1) but high in adenomatous ones (grades 2 and 3). Bcl-2 expression was also low in patients with HT (grade 1). CONCLUSION: It is concluded that in comparison to HT, where there is up-regulation of Fas and down-regulation of Bcl-2 protein, Fas expression is low in human goiter, indicating low apoptotic activity. The regulation of Bcl-2 protein differs between adenomatous and colloid nodules, suggesting that this protein may play a role in the differentiation of thyroid nodules.     

Natural course of autoimmune thyroiditis after elimination of iodine deficiency in northwestern Greece.

We have previously reported the elimination of iodine deficiency and increasing prevalence of autoimmune thyroiditis (AIT) among schoolchildren in northwestern Greece. This study followed up 29 children (12-18 years old) with AIT for 5 years to track its course in the postiodination era. At diagnosis, thyroid peroxidase autoantibodies (TPOAbs) were positive in 25 children (86%) and became positive in all children during follow-up. Thyroglobulin autoantibodies (TgAbs) were positive in 17 children at diagnosis (59%) and became positive in 3 more children (69%). Both antibody types increased by the end of the observation period (p < 0.005). Regarding thyroid function, 7 children (24%) at diagnosis had subclinical hypothyroidism that persisted and 4 more children developed subclinical hypothyroidism during the study period (38%). Only 5 of these children (45%) had positive TgAbs. There was an increase in thyrotropin (TSH) so that at the end of the study all children had TSH greater than 2.5 mU/L but none developed overt hypothyroidism. Thyroid hypoechogenicity that increased over time was seen in all children, especially in those with subclinical hypothyroidism. In conclusion, both antibody types increased in frequency and level, but TPOAbs were the predominant autoimmunity marker predictive of impending thyroid failure in children with AIT, as was thyroid hypoechogenicity on ultrasound.     

The role of estrogens in cardiovascular disease in the aftermath of clinical trials

The effects of estrogens on reproductive tissues and climacteric symptoms are unambiguous. However, their effects on other tissues and, in particular, the cardiovascular system remain controversial. In general, premenopausal women are protected from coronary heart disease (CHD) compared with aged-matched men but this ;female protection' appears to be lost after menopause, suggesting beneficial effects of female sex hormones on the cardiovascular system. This view has been supported by observational studies showing that estrogen replacement therapy (ERT) is associated with a 30% to 50% decrease in CHD risk in postmenopausal women. Nevertheless, randomized clinical trials in postmenopausal women, with or without pre-existing CHD, have found no benefits to combined hormone replacement therapy (HRT). A possible explanation for these apparently contradictory findings may relate to the divergent effects of estrogens depending on the state of the vascular endothelium. It has been suggested that estrogens may prevent the development and early progression of atherosclerosis by contributing to the maintenance of endothelial health but may have a neutral or negative effect on a dysfunctional endothelium or on advanced atheromatous lesions. Furthermore, it is possible that estrogens have adverse effects on other cardiovascular risk factors such as thrombosis and inflammation. It is also conceivable that a decline in vascular estrogen receptor expression with advancing age, through methylation of the estrogen receptor promoter, prevents postmenopausal women from deriving the beneficial cardiovascular effects of estrogens. In conclusion, estrogens possibly prevent the development of atherosclerosis through favourable effects on an intact endothelium, but once the vascular endothelium is damaged, the prothrombotic and possibly proinflammatory effects of estrogens are likely to predominate and prove harmful.     

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.     

The role of Hemochromatosis C282Y and H63D mutations in the development of type 2 diabetes mellitus in Greece

Several authors have suggested a positive association between diabetes type 2 (DM2) and the C282Y and H63D mutations of the hereditary hemochromatosis gene but others have disputed it. There are also papers reporting an increased iron load in diabetes type 2 and a possible association with the pathogenesis of the disease. We therefore performed a study in 100 type 2 diabetics and 100 age and sex matched controls to assess the possibility that C282Y and H63D mutations constitute a risk factor for DM2 in Greece. We also evaluated the iron load in 500 diabetes type 2 patients and 423 age and sex matched controls. We did not find any differences in the allele frequencies of the above mutations between patients with diabetes type 2 and controls. The allele frequencies were estimated to be 0.0075 for the C282Y and 0.115 for the H63D mutation. Subjects with even one mutation (C282Y or H63D) had higher transferrin saturation compared to those with no such mutations. This seems to apply to both diabetics (49+/- 8,6 vs 44,5+/- 5,4, p<0,01) and controls (49,3+/- 7,3 vs 42,6+/- 3,3 p<0,01). Patients with DM2 had higher transferrin saturation compared to the general population. These differences were found among men (n=250, mean+/- SD 31,8+11 vs n=73, mean+/- SD 29,5+8, p=0,05) as well as among women (n=250, mean+/- SD 28.5+10 vs n=350, mean+/- SD 25.5+9.6, p=0.001). The DM2 patients had higher ferritin levels compared to controls. In conclusion, DM2 patients have increased iron load. The C282Y and H63D mutations contribute to increased iron load in both DM2 and controls. There was no difference in the frequency of C282Y and H63D alleles between DM2 and controls in the Hellenic population.     

Turner's syndrome with concomitant hypopituitarism: case report

The unique case of a young woman with concomitant pituitary insufficiency and gonadal dysgenesis due to Turner's syndrome is described. At the age of 17 years, when first examined elsewhere, this patient was prepubertal and short and a diagnosis of growth hormone deficiency was made. One year later, while on growth hormone (GH) substitution, thyrotrophin deficiency and hypogonadotrophic hypogonadism were confirmed and thyroxine and sex steroid substitution therapy was initiated. Upon evaluation in our clinic, at the age of 30 years, the low final height achieved with the GH substitution therapy, a number of clinical characteristics and the absence of ovarian tissue on ultrasound led to examination of the patient's karyotype, which revealed concurrent gonadal dysgenesis due to Turner's syndrome. This case illustrates that the co-existence of primary and secondary hypogonadism may obscure and delay the diagnosis of Turner's syndrome, a diagnosis which alters the counselling of the patient from the reproductive perspective.