Pathophysiology of impaired ovarian function in galactosaemia

Abstract

Classical galactosaemia is an inherited inborn error of the major galactose assimilation pathway, caused by galactose-1-phosphate uridyltransferase (GALT) deficiency. Many GALT mutations have been described, with different clinical consequences. In severe forms, newborns present with a life-threatening, acute toxic syndrome that rapidly regresses under a galactose-restricted diet. However, long-term complications, particularly cognitive and motor abnormalities, as well as hypergonadotrophic hypogonadism in female patients are still unavoidable. The pathogenesis of galactose-induced ovarian toxicity remains unclear but probably involves galactose itself and its metabolites such as galactitol and UDP-galactose. Possible mechanisms of ovarian damage include direct toxicity of galactose and metabolites, deficient galactosylation of glycoproteins and glycolipids, oxidative stress and activation of apoptosis. As there is no aetiological treatment, clinical management of ovarian failure in galactosaemic patients principally relies on hormonal replacement therapy to induce pubertal development and to prevent bone loss and other consequences of estrogen deprivation. Further investigations will be necessary to better understand the metabolic flux of galactose through its biochemical pathways and the mechanisms of these secondary complications. The aim of this article is to present an extensive review on the pathogenesis and clinical management of galactose-induced premature ovarian failure.

The effect of monosaccharide sugars and pyruvate on the differentiation and metabolism of sheep granulosa cells in vitro

“…The main products of galactose metabolism are glucose (in the form of glucose-1-phosphate which then enters the glycolytic pathway) and UDP-galactose, which is required for glycoconjugation of proteins and lipids (Forges et al 2006). In contrast to fructose, a number of SLC2As that transport galactose (GLUT1, GLUT2, GLUT3 and GLUT8) have been reported in the ruminant ovary ((Nishimoto et al 2006;GLUT1 and GLUT3); (Pisani et al 2008;GLUT1, GLUT3 and GLUT8); (Williams et al 2001;GLUT1)).…”

“…The accumulation of galactose or its metabolites is associated with impaired ovarian function in the human, which arises typically because of a deficiency or a mutation of galactose-1-phosphate uridyltransferase, one of the key enzymes required for the metabolism of galactose. The pathogenesis of this ovarian dysfunction is unclear, but in addition to direct toxicity, it includes deficient galactosylation of glycoproteins and glycolipids, induction of apoptosis and modulation of the expression of intra-ovarian growth factors such as growth differentiation factor 9 (Forges et al 2006). These toxic effects of galactose on ovarian function are consistent with our observed inhibitory effects of high doses of galactose on FSH-induced differentiation of granulosa cells and the fact that direct ovarian infusion of galactose in sheep led to a depression in ovarian E 2 and androstenedione secretion (Onions et al 2009).…”

An update on primary ovarian insufficiency

“…Severe phenotypes lead to lethal toxic syndrome and cognitive and motor abnormalities [75]. 17%-67% galactosemic women are reported to have POI [71,76], and studies show that classic galactosaemia leads to varied level of ovarian dysfunction in different individuals [77].…”

“…It have been hypothesized that the accumulation of galactose and its toxic metabolites (galactose-I-phosphate and galactitol) after birth (since toxic metabolites in fetus should be cleared rapidly by maternal enzymes) leads to direct ovarian damage. Apart from this, hypoglycosylation of glycoproteins or glycolipids, oxidative stress and activation of apoptosis could result in FSH dysfunction [15,75,81]. Gubbels et al [75] compared the FSH isoform patterns between 5 galactosaemia patients, one PMM2-CDG (a primary glycosylation disorder) patients, and 5 naturally postmenopausal women, finding that less acidic isoform of serum FSH due to hypoglycosylation is not significantly related to the development of POI.…”

“…Apart from this, hypoglycosylation of glycoproteins or glycolipids, oxidative stress and activation of apoptosis could result in FSH dysfunction [15,75,81]. Gubbels et al [75] compared the FSH isoform patterns between 5 galactosaemia patients, one PMM2-CDG (a primary glycosylation disorder) patients, and 5 naturally postmenopausal women, finding that less acidic isoform of serum FSH due to hypoglycosylation is not significantly related to the development of POI. Autoimmune mechanisms might also be involved, but no antibodies have been reported yet.…”