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Persani L.,University of Milan | Persani L.,Laboratorio Of Ricerche Endocrinologiche | Rossetti R.,University of Milan | Cacciatore C.,Laboratorio Of Ricerche Endocrinologiche
Journal of Molecular Endocrinology | Year: 2010

Premature ovarian failure (POF) is an ovarian defect characterized by the premature depletion of ovarian follicles before the age of 40 years, representing one major cause of female infertility. POF relevance is continuously growing because women tend to conceive ever more frequently in their thirties and forties. POF can present very early with a pubertal defect. More frequently, it is the end stage of an occult process (primary ovarian insufficiency, POI) affecting ∼1-2% of under-40 women. POI is a heterogeneous disease caused by a variety of mechanisms. Though the underlying cause remains unexplained in the majority of cases, various data indicate that POI has a strong genetic component. These data include the existence of several causal genetic defects in humans, experimental and natural models, as well as the frequent familiarity. The variable expressivity of POI defect in women of the same family may indicate that, in addition to some monogenic forms, POI may frequently be considered as a multifactorial defect resulting from the contribution of several predisposing alleles. The X chromosome-linked defects play a major role among the presently known causal defects. Here, we review the principal X-linked and autosomal genes involved in syndromic and nonsyndromic forms of POI with the wish that this list will soon become upgraded because of the discovery of novel contributing mechanisms. A better understanding of POI pathogenesis will indeed allow the construction of tests able to predict the age of menopause in women at higher risk of POI. © 2010 Society for Endocrinology. Source

Persani L.,University of Milan | Persani L.,Laboratorio Of Ricerche Endocrinologiche | Calebiro D.,University of Milan | Calebiro D.,Laboratorio Of Ricerche Endocrinologiche | And 9 more authors.
Molecular and Cellular Endocrinology | Year: 2010

The resistance to thyrotropin (TSH) action is the disease associated with molecular defects hampering the adequate transmission of TSH stimulatory signal into thyroid cells. The defect may in principle affect every step along the cascade of events following the binding of TSH to its receptor (TSHR) on thyroid cell membranes. After the description of the first family affected with loss-of-function (LOF) TSHR mutations in 1995, there is now evidence that TSH resistance is a disease with a broad range of expressivity going from severe congenital hypothyroidism (CH) with thyroid hypoplasia to mild hyperthyrotropinemia (hyperTSH) associated with an apparent euthyroid state. More severe forms occur in patients with disrupting biallelic TSHR mutations and follow a recessive pattern of inheritance. Differential diagnosis in these cases includes the exclusion of other causes of thyroid dysgenesis, such as mutations in thyroid transcription factors. More mild forms may instead occur in patients with monoallelic TSHR defects following a dominant mode of inheritance. In these cases we described the dominant negative effect exerted by some LOF mutants on the activity of the wild-type TSHR. Differential diagnosis involves the exclusion of mild hypothyroidism in autoimmune thyroid disease or pseudohypoparathyroidism associated with genetic or epigenetic defects at the GNAS locus. This review will focus on the prevalence of TSHR mutations, on the molecular mechanisms leading to TSH resistance and on the variable clinical expression of this disease. © 2010 Elsevier Ireland Ltd. Source

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