Pathophysiology and management of classic galactosemic primary ovarian insufficiency

Classic galactosemia is an inborn error of carbohydrate metabolism associated with early-onset primary ovarian insufficiency (POI) in young women. Our understanding of the consequences of galactosemia upon fertility and fecundity of affected women is expanding, but there are important remaining gaps in our knowledge and tools for its management, and a need for continued dialog so that the special features of the condition can be better managed. Here, we review galactosemic POI and its reproductive endocrinological clinical sequelae and summarize current best clinical practices for its management. Special consideration is given to the very early-onset nature of the condition in the pediatric/adolescent patient. Afterward, we summarize our current understanding of the reproductive pathophysiology of galactosemia, including the potential action of toxic galactose metabolites upon the ovary. Our work establishing that ovarian cellular stress reminiscent of endoplasmic reticulum (ER) stress is present in a mouse model of galactosemia, as well as work by other groups, are summarized. LAY SUMMARY: Patients with the condition of classic galactosemia need to maintain a strict lifelong diet that excludes the sugar galactose. This is due to having mutations in enzymes that process galactose, resulting in the buildup of toxic metabolic by-products of the sugar. Young women with classic galactosemia often lose the function of their ovaries very early in life (termed 'primary ovarian insufficiency'), despite adherence to a galactose-restricted diet. This means that in addition to the consequences of the disease, these women also face infertility and the potential need for hormone replacement therapy. This article summarizes current strategies for managing the care of galactosemic girls and women and also what is known of how the condition leads to early primary ovarian insufficiency.