Osteoporosis in celiac disease and in endocrine and reproductive disorders.

As the increase in lifespan brings to light diseases that were previously not clinically detectable, osteoporosis has become an issue of worldwide significance. The disease is marked by a loss of bone mass; the bones become less dense, fragile and more prone to fracturing. Because it is regulated by endocrine and environmental factors, osteoporosis presents a multifactorial etiopathogenesis, with the genetic component accounting for 70% of an individual variation in bone mass density (BMD), the principal determinant, with age, of fracture risk. Pathological conditions such as celiac disease (CD) exacerbate the process of bone loss, so that the occurrence of osteoporosis in celiac subjects is of particular note: indeed, the screening of osteoporosis patients for this disease is advisable, since it may be the only sign of undiagnosed CD. An increase in interleukin IL-1beta, of the IL-1 system, in the relatives of celiac patients confirms the genetic predisposition to osteoporosis and its presence is evidence of an association between the two conditions. The direct effect on the bones of CD is secondary to poor absorption of calcium and vitamin D. In women osteoporosis is indirectly associated with early menopause and amenorrhea, and it may follow prolonged breast-feeding and frequent pregnancies, while in men it is associated with hypogonadism and GH deficit. These endocrine and non-endocrine factors exert their effects on bones by modulating the RANK/RANK-L/OPG system. An appropriate lifestyle from adolescence onwards, together with early diagnosis of and treatment for CD and primary and secondary endocrine pathologies are important for the prevention of damage to the bones.

Risk of osteoporosis in endocrine disorders and celiac disease.

Osteoporosis is characterized by a loss of bone mass; the bones become less dense, fragile and prone to fracturing. It is regulated by endocrine-environmental factors with the genetic component accounting for 70% of an individual's variation in bone mass density (BMD). Pathological conditions such as celiac disease (CD) exacerbate the process of bone loss and the presence of osteoporosis in celiac subjects may be the only sign of undiagnosed CD. The interleukins IL-1alpha and IL-1beta are stimulators of bone resorption; the relatives of celiac patients shown the increased IL-1beta supporting the genetic susceptibility. In women osteoporosis is indirectly associated with early menopause and amenorrhea, while in men it is associated with hypogonadism and GH deficit. The direct effect on the bones of CD is secondary to poor absorption of calcium and vitamin D. These endocrine and non-endocrine factors exert their effects on bones by modulating the RANK/RANK-L/OPG system.

[Reproductive aspects of celiac disease]. / Aspetti riproduttivi della malattia celiaca.

In the past, celiac disease (CD), or intolerance to gluten, was considered a rare disease of infancy characterized by chronic diarrhea with malabsorption and delayed growth. Besides the overt enteropathy, there are other clinic and subclinical forms which appear later in life. Target organs are not limited to the gut, but include liver, thyroid, skin and female and male reproductive systems. CD interference on reproduction is related to the multifactorial nature of the disease, whose pathological manifestations can be modulated, besides gluten, by different concurrent genetic and environmental factors. CD induces malabsorption with consequent deficiencies of micronutrients such as iron, folic acid and vitamin K, which are essential for organogenesis, and fat-soluble vitamins important for spermatogenesis. Regarding endocrine disorders, the deficiencies of specific trace elements on ovarian function could explain its involvement in the increased risk of female osteoporosis in CD patients. Affected males show a picture of tissue resistance to androgens; the increases of follicle-stimulating hormone and prolactin, not associated with infertility, may indicate an imbalance at hypothalamus-pituitary level, with general effects on health. Since reproductive alterations are reversible, adoption of a gluten-free diet supported by early diagnosis is important. Therefore, the detection of early biomarkers, such as deficiencies of vitamins and/or iron and andrological or endocrinological dysfunctions, should trigger timely strategies for prevention and treatment.

[Coeliac disease and reproduction: possible in vivo models]. / Malattia celiaca e riproduzione: possibili modelli in vivo.

Presently there are no in vivo models to study the different effects of coeliac disease (CD) including the increase of reproductive risks. CD is a multifactorial condition which requires both an exogenous element (gluten) and complex genetic factors; moreover, CD is associated to several endocrine, immune and reproductive diseases. There are no adequate in vivo models for the systemic complications of CD; in particular, there are no genetic knock-out models. However, models are available for gluten enteropathy such as Irish Setter and Balb/c and BDF1 mouse strains, and also for endocrine-immune diseases associated to CD such as BB rats and NOD mice. These models could be used to study reproductive aspects. This is desirable because a new model for dermatitis herpetiformis tightly associated with CD, that uses HLA-DQ8 transgenic NOD mice, has already been identified.

Histological and histomorphometric alterations in thyroid and adrenals of CD rat pups exposed in utero to methyl thiophanate.

Pregnant CD rats were treated with an initial dose of 0, 310 or 560 mg/kg bw per day of the fungicide methyl thiophanate (MT) on gestational days 10-14, corresponding to formation of thyroid and adrenal primordia; newborns were sacrificed on postnatal days (PNDs) 10 and 23. No apparent maternal toxicity and no effects on litter size, viability or weight gain were present. Delayed ear pinna detachment and eye opening were present at top dose level. Thyroid histology showed increased irregular nuclei and/or mitoses (PND 10-both doses), cells with necrotic or hydropic changes (PND 23-top dose). The adrenal cortex showed increased karyomegaly and hydropic degeneration (PND 23-both doses). Thyroid histomorphometry showed reduced follicular density, moderately increased follicular cell height and number of nuclei/follicle (PND 10-top dose and PND 23-both doses), suggesting retarded follicular maturation. The adrenal cortex relative area was slightly decreased (PND 10-top dose and PND 23-both doses).MT may act as weak endocrine disrupter, suggesting that attention should be paid to delayed endocrine alterations elicited by agrochemicals.

Long-lasting effects of lindane on mouse spermatogenesis induced by in utero exposure.

Long-lasting effects on mouse spermatogenesis induced by prenatal exposure to the insecticide lindane have been investigated by conventional reproductive endpoints complemented by the flow cytometric (FCM) DNA content analysis of testis cells and by the Sperm Chromatin Structure Assay (SCSA). Two lindane dose levels, 15 and 25 mg/kg bw, and diethylstilboestrol (DES, 10 microg/kg bw) as positive control, were administered daily by gavage to pregnant CD1 mice on gestation days (GD) 9-16. Reproductive endpoints were evaluated on F1 male mice on postnatal day (PND) 60; additionally, animals treated with lindane 25 mg/kg per day and DES were examined on PND 100 to evaluate the possible reversibility of the effects. On PND 60, lindane and DES caused a reduction in the sperm head count and concentration, with recovery in older lindane 25 mg/kg per day animals (PND 100). By contrast, the DES group exhibited a greater reduction in the sperm head count on PND 100 than on PND 60. Changes in biochemical parameters in the testes, lactate dehydrogenase-C(4) (LDH-C(4)), and sorbitol dehydrogenase (SDH) activities, were also observed in adult treated F1 mice. Furthermore on PND 60, the FCM analysis revealed changes in the pattern of testicular germ cell distribution, especially in the haploid subcompartment, in the lindane 25 mg/kg per day group. A dose-dependent increase in chromatin abnormalities of the epididymal sperm was also shown by SCSA. These changes recovered on PND 100. Preliminary qualitative examination did not reveal any significant difference in the structure of testicular tissue; however, there were suggestions of a moderate increase in number and size of Leydig cells in both DES- and lindane-treated animals. The partial reversibility of these effects and the lack of structural modification of the testicular tissue as evidenced by histopathologic assessment suggest a functional impairment of sperm production and maturation, possibly associated with changes induced by lindane on factors affecting intratesticular steroidogenesis.

Selenium status and over-expression of interleukin-15 in celiac disease and autoimmune thyroid diseases.

In celiac disease (CD), for its multifactorial nature, the target organs are not limited to the gut, but include thyroid, liver, skin and reproductive and nervous systems. Between the extraintestinal symptoms associated with CD, autoimmune thyroid diseases (AITDs) are more evident, underlining as CD-related autoimmune alterations can be modulated not only by gluten but also by various concurrent endogenous (genetic affinity, over-expression of cytokines) and exogenous (environment, nutritional deficiency) factors. In their pathogenesis a central role for over-expression of interleukin-15 (IL-15) is shown, by inhibiting apoptosis, leading to the perpetuation of inflammation and tissue destruction. Thyroid is particularly sensitive to selenium deficiency because selenoproteins are significant in biosynthesis and activity of thyroid hormones; besides, some selenoproteins as glutathione peroxidase are involved in inhibiting apoptosis. Thus, selenium malabsorption in CD can be thought as a key factor directly leading to thyroid and intestinal damage. Considering the complexity of this interaction and on the basis of available evidence, the aim of this review is to assess as preventive and therapeutic target the role of IL-15 and selenium in the pathogeneses of both CD and AITD.