The hypergonadotropic hypogonadism conundrum of classic galactosemia

Abstract

BACKGROUND Hypergonadotropic hypogonadism is a burdensome complication of classic galactosemia (CG), an inborn error of galactose metabolism that invariably affects female patients. Since its recognition in 1979, data have become available regarding the clinical spectrum, and the impact on fertility. Many women have been counseled for infertility and the majority never try to conceive, yet spontaneous pregnancies can occur. Onset and mechanism of damage have not been elucidated, yet new insights at the molecular level are becoming available that might greatly benefit our understanding. Fertility preservation options have expanded, and treatments to mitigate this complication either by directly rescuing the metabolic defect or by influencing the cascade of events are being explored. OBJECTIVE AND RATIONALE The aims are to review: the clinical picture and the need to revisit the counseling paradigm; insights into the onset and mechanism of damage at the molecular level; and current treatments to mitigate ovarian damage. SEARCH METHODS In addition to the work on this topic by the authors, the PubMed database has been used to search for peer-reviewed articles and reviews using the following terms: ‘classic galactosemia’, ‘gonadal damage’, ‘primary ovarian insufficiency’, ‘fertility’, ‘animal models’ and ‘fertility preservation’ in combination with other keywords related to the subject area. All relevant publications until August 2022 have been critically evaluated and reviewed. OUTCOMES A diagnosis of premature ovarian insufficiency (POI) results in a significant psychological burden with a high incidence of depression and anxiety that urges adequate counseling at an early stage, appropriate treatment and timely discussion of fertility preservation options. The cause of POI in CG is unknown, but evidence exists of dysregulation in pathways crucial for folliculogenesis such as phosphatidylinositol 3-kinase/protein kinase B, inositol pathway, mitogen-activated protein kinase, insulin-like growth factor-1 and transforming growth factor-beta signaling. Recent findings from the GalT gene-trapped (GalTKO) mouse model suggest that early molecular changes in 1-month-old ovaries elicit an accelerated growth activation and burnout of primordial follicles, resembling the progressive ovarian failure seen in patients. Although data on safety and efficacy outcomes are still limited, ovarian tissue cryopreservation can be a fertility preservation option. Treatments to overcome the genetic defect, for example nucleic acid therapy such as mRNA or gene therapy, or that influence the cascade of events are being explored at the (pre-)clinical level. WIDER IMPLICATIONS Elucidation of the molecular pathways underlying POI of any origin can greatly advance our insight into the pathogenesis and open new treatment avenues. Alterations in these molecular pathways might serve as markers of disease progression and efficiency of new treatment options.

Premature ovarian insufficiency in patients with galactosemia

“…Причины развития ПНЯ при КГ неизвестны, но данные свидетельствуют о нарушении регуляции путей, имеющих решающее значение для фолликулогенеза, таких как PI3K/AKT, пути инозитола, MAPK, передача сигналов IGF-1 и TGF-β [8]. Также в ходе исследований на модели мыши GalTKO были получены данные, свидетельствующие о ранних молекулярных изменениях в виде нарушения интегрированной реакции на стресс (ISR), вызывающей ускоренную активацию роста примордиальных фолликулов в раннем возрасте с их «выгоранием», что напоминает наблюдаемую у пациенток прогрессирующую недостаточность яичников [9].…”

“…При КГ характерным является снижение уровня антимюллерова гормона по сравнению со здоровыми контрольными группами соответствующего возраста [13], что выявляется даже у очень молодых пациенток (до 1 года). АМГ выполняет ключевую функцию в регуляции роста и развития фолликулов, следовательно, низкие уровни АМГ отражают снижение овариального резерва [8]. В данных клинических случаях у обеих пациенток уровень АМГ был снижен.…”

Research Progress on the Pathogenesis of Premature Ovarian Failure: A Review

“…Galactose-1-phos-phate Uri-dyltransferase (GALT) is a key enzyme in lactose metabolism, and GALT deficiency leads to the accumulation of D-galactose in the body, which reacts with free amines from amino acids in proteins and peptides to form glycosylation end products (advanced glycation end products, AGEs), which ultimately produce acetaldehyde and hydrogen peroxide in the presence of galactose oxidase, thereby increasing ROS levels and leading to cellular aging [101]. Higher levels of galactose cause patients to exhibit high gonadotropin levels, and abnormal metabolites can also directly damage the ovarian parenchyma [102]. In the absence of 17-OHD, pregnenolone cannot be converted to 17α-hydroxypregnenolone, which leads to a decrease in the secretion of sex hormones, such as cortisol, androstenedione, testosterone, and estrogen [103], which in turn affects the normal function of the ovaries.…”

Natural history of three late-diagnosed classic Galactosemia patients

“…Untreated, it can result in neonatal life-threatening complications, including feeding problems, failure to thrive, hepatocellular damage, bleeding, and E coli sepsis [ 1 , 2 ]. A galactose-restricted diet, reported for the first time in 1935, resolves the neonatal clinical picture, but later on most patients develop complications affecting mainly the central nervous system and the female gonads [ [3] , [4] , [5] , [6] , [7] , [8] ]. This results in cognitive, neurological and behavioral disability, primary ovarian insufficiency (POI), and subsequent subfertility in female patients [ 9 , 10 ].…”