Presentation, progression, and predictors of ovarian insufficiency in classic galactosemia

Abstract

Classic galactosemia (CG) is an inherited metabolic disorder that affects about 1 in 50,000 live births in the United States and many other countries. With the benefit of early detection by newborn screening and rapid dietary restriction of galactose, generally achieved by removing dairy from the diet, most affected infants are spared the acute and potentially lethal symptoms of disease. Despite early detection and life-long dietary intervention, however, most patients grow to experience a constellation of long-term complications that include premature ovarian insufficiency in the vast majority of girls and young women. Our goal in the study reported here was to define the presentation, progression, and predictors of ovarian insufficiency in a cohort of 102 post-pubertal girls and women with CG. To our knowledge, this is the largest cohort studied to date. We found that 68% of the girls and women in our study achieved spontaneous menarche, while 32% achieved menarche only after starting hormone replacement therapy (HRT). Of those who achieved spontaneous menarche, fewer than 50% were still cycling regularly after 3 years, and fewer than 15% were still cycling regularly after 10 years. Of factors tested for possible association with spontaneous menarche, only detectable (≥ 0.04 ng/mL) plasma anti-Müllerian hormone (AMH) level was significant. These results extend substantially from prior studies and confirm that detectable plasma AMH is a useful predictor of ovarian function in girls and women with CG.

Figure 1. Age at menarche of cases and controls in this study

Age at menarche, in years, was reported for each volunteer as a whole number (e.g.15, not 15.2). The average age at menarche for controls was 12.8 years, for cases with spontaneous menarche was 13.8 years, and for cases with HRT-assisted menarche was 14.2 years.

Figure 2. Years of regular menstrual cycles after spontaneous menarche

About half of young women with CG who achieved spontaneous menarche were still cycling regularly after 3 years; only about 35% were still cycling regularly after 5 years, and fewer than 15% were still cycling regularly after 10 years. In the Kaplan-Meier curve presented, the solid line represents the estimated "survival" function, and the dashed lines present the 95% confidence interval.

Figure 3. Average plasma AMH and FSH levels in girls and women with CG who achieved spontaneous versus HRT-assisted menarche

Plasma AMH ≥0.04ng/mL (panel A) associated strongly with spontaneous menarche (p=0.0009) but plasma FSH (panel B) did not (p=0.7871).

Figure 4. Age at initiation of HRT

The majority of girls and women in our study initiated HRT either to promote or complete puberty, or to manage peri-menopausal symptoms. As expected, we saw a range of ages in both groups, but as a whole those in the first group were pre-teens and teens, and those in the second group were in their older teens or 20s.