Primary ovarian insufficiency in classic galactosemia: current understanding and future research opportunities

Abstract

Classic galactosemia is an inborn error of the metabolism with devastating consequences. Newborn screening has been successful in markedly reducing the acute neonatal symptoms from this disorder. The dramatic response to dietary treatment is one of the major success stories of newborn screening. However, as children with galactosemia achieve adulthood, they face long-term complications. A majority of women with classic galactosemia develop primary ovarian insufficiency and resulting morbidity. The underlying pathophysiology of this complication is not clear. This review focuses on the reproductive issues seen in girls and women with classic galactosemia. Literature on the effects of classic galactosemia on the female reproductive system was reviewed by an extensive Pubmed search (publications from January 1975 to January 2017) using the keywords: galactosemia, ovarian function/dysfunction, primary ovarian insufficiency/failure, FSH, oxidative stress, fertility preservation. In addition, articles cited in the search articles and literature known to the authors was also included in the review. Our understanding of the role of galactose metabolism in the ovary is limited and the pathogenic mechanisms involved in causing primary ovarian insufficiency are unclear. The relative rarity of galactosemia makes it difficult to accumulate data to determine factors defining timing of ovarian dysfunction or treatment/fertility preservation options for this group of women. In this review, we present reproductive challenges faced by women with classic galactosemia, highlight the gaps in our understanding of mechanisms leading to primary ovarian insufficiency in this population, discuss new advances in fertility preservation options, and recommend collaboration between reproductive medicine and metabolic specialists to improve fertility in these women.

Keywords: Classic galactosemia; Fertility preservation; Galactose metabolism; Ovarian dysfunction; Primary ovarian insufficiency.

Fig. 1

Pathway of galactose metabolism (simplified). GALE, UDP galactose 4′-epimerase; GALK, galactokinase; GALT, galactose-1-P uridyltransferase; P, phosphate; UDP, uridine diphosphate; broken lines show pathway with multiple enzymatic steps

Fig. 2

Proposed mechanisms of primary ovarian insufficiency (POI) in classic galactosemia: A scheme of development of POI in women with classic galactosemia based on the current evidence is proposed. Galactose and its metabolites have been implicated in toxic damage to the ovaries. The timing of this damage remains unclear. In addition, abnormalities in follicle-stimulating hormone or its receptor and disturbances in epigenetic mechanisms have also been suggested to cause POI