The most common long-term complication reported for girls and women with profound GALT deficiency is POI, with an incidence of >80% and perhaps >90% (e.g., Kaufman et al.
1981; Waggoner et al.
1990; reviewed in Berry
2008; Fridovich-Keil and Walter
2008; Rubio-Gozalbo et al.
2010). Of note, patients with trace levels of residual GALT activity may demonstrate a milder phenotype (Berry
2008; Guerrero et al.
2000; Kaufman et al.
1988), leading to confusion or controversy in some instances. There have been no reports of ovarian dysfunction among women with Duarte galactosemia (who demonstrate about 25% normal GALT activity), and a cohort of galactosemia carrier women demonstrated apparently normal ovarian reserve and age at menopause (Knauff et al.
2007), although many of the women in that study were ascertained on the basis of their children, meaning there may have been a bias in the cohort toward women who were (or had been) fertile.
POI detection in prepubertal girls with classic galactosemia
Because of its prevalence in the patient population, there has been considerable interest in presymptomatic diagnosis of POI among prepubertal girls with classic galactosemia. Until recently, the only minimally invasive approach involved measurement of blood FSH values and estradiol values. However, FSH is an indirect measure, reflecting the hypothalamic response to diminished ovarian function, and this response may be absent in prepubertal girls. Ovarian imaging studies in prepubertal girls might also be informative, but these are more complex and are not routinely performed, especially on very young girls.
Recently we reported data suggesting that anti-Müllerian hormone (AMH), which is produced by granulosa cells of primary through late preantral and preovulatory follicles (La Marca and Volpe
2006), may provide a meaningful predictor of ovarian function in prepubertal girls with classic galactosemia (Sanders et al.
2009). In nongalactosemic women, AMH levels correlate with antral follicle counts visible by ultrasound and also with histologically determined primordial follicle counts (Hansen et al.
2010). While the reported results with galactosemic girls were promising, longitudinal studies will be needed to test the true predictive value of serum or plasma AMH levels measured in this population.
Timing of the onset of POI in galactosemia
POI in galactosemia may manifest as primary amenorrhea, secondary amenorrhea, or oligomenorrhea. Explanations for any of these outcomes could include a reduced initial oocyte pool, increased follicular atresia during development, or perhaps diminished maturation of primordial follicles. Determining the point in development at which POI begins has been difficult; whether the fundamental defect arises prenatally, in infancy, or later in childhood, ovarian insufficiency is not clinically apparent until puberty. Furthermore, a GALT-deficient animal model has not yet been reported that recapitulates the reproductive phenotype. However, results from numerous studies suggest that galactosemia-associated ovarian dysfunction has its roots in early development.
Newborn screening for galactosemia and prenatal diagnosis have allowed for early initiation of dietary galactose restriction; unfortunately, these advances have not led to a reduced incidence of POI in galactosemia (Rubio-Gozalbo et al.
2006; Schweitzer et al.
1993; Waggoner et al.
1990). The failure of dietary galactose restriction to improve reproductive outcomes suggests that GALT deficiency may first affect ovarian tissue in the pre- or perinatal period, prior to diagnosis and intervention. Those animal studies that have been reported support this hypothesis. In genetically wild-type rats, prenatal exposure to a high level of galactose has been shown to interfere with the migration of primordial germ cells to the developing gonad (Bandyopadhyay et al.
2003), and female pups demonstrate reduced initial oocyte pools (Chen et al.
1981).
Galactosemic females are undoubtedly exposed to galactose prenatally: galactose, galactitol, and gal-1-P levels have all been detected at abnormally high levels in the tissues of galactosemic fetuses (Holton
1995). This accumulation in utero is most likely due to self-intoxication from de novo galactose synthesis. Leloir enzyme activity is detectable in the human fetal liver by the 10th week of gestation (Holton
1995), and maternal adherence to a lactose-restricted diet does not prevent accumulation of galactose metabolites in the cord blood (Irons et al.
1985) or amniotic fluid (Jakobs et al.
1988) of galactosemic newborns.
Studies of serum biomarkers used to assess ovarian status in galactosemic girls also suggest that galactosemia-associated POI begins in early life. Serum AMH levels, used clinically as an indicator of follicular function and ovarian reserve (La Marca and Volpe
2006), are abnormally low in galactosemic girls relative to age-matched controls, even in girls younger than 2 years (Sanders et al.
2009). Elevated FSH level, an indirect measure of ovarian function, has been observed in galactosemic girls as early as 10 months of age and may remain high throughout the prepubertal years (Beauvais and Guilhaume
1984; Gitzelmann and Steinmann
1984; Irons et al.
1986; Kaufman et al.
1986; Schwarz et al.
1986; Steinmann et al.
1981; reviewed in Berry
2008; Rubio-Gozalbo et al.
2006,
2010). FSH production in response to GnRH stimulation is also abnormally high in classic galactosemics (reviewed in Berry
2008).
Combined, these findings suggest that the ovaries of most galactosemic girls are already functionally different in neonatal life with possible toxicity starting in fetal life. This may lead to fewer follicles at birth resulting in accelerated depletion of follicles in this population of girls and women. However, FSH measurements in prepubertal girls may be misleading. For example, prior to the age of 2 years an elevated FSH level may reflect factors independent of ovarian function of the child, and even a normal FSH level in a prepubertal girl is not fully reassuring since the hypothalamic-pituitary-ovarian (HPO) axis is thought to be quiescent after 1–2 years of age and not fully reactivated until just prior to puberty (Conte et al.
1975). Whether timing of the HPO axis is altered in galactosemic girls remains unclear. Thus, depending on whether the HPO axis is active in a given prepubertal girl, her FSH levels may not start to rise until early puberty even if her ovaries are dysfunctional.
Morphologic and histologic studies of ovaries from galactosemic girls might provide more insight into the timing of onset of ovarian dysfunction, but the limited studies that have been published are mostly confined to women in whom POI had already been diagnosed. In two case reports concerning prepubertal girls, the ovaries appeared normal; postmortem examination of a galactosemic newborn who died of
E. coli sepsis revealed morphologically normal ovaries containing abundant oocytes (Levy et al.
1984), and a 7-year-old girl undergoing ultrasound for appendicitis was also found to have ovaries that appeared normal. Intriguingly, this same girl was later diagnosed with POI and underwent laparoscopy at age 17, which revealed streak ovaries (Kaufman et al.
1981). In imaging studies of girls with POI examined at pubertal age or later, the ovaries are invariably abnormal and usually described as hypoplastic or “streak-like.” Histological examination most often shows few if any follicles; in the cases where follicles have been observed they did not appear to have matured beyond the primordial stage (reviewed in Rubio-Gozalbo et al.
2010).
Lack of information on ovarian morphology and histology in a majority of galactosemic girls in infancy and early childhood makes it impossible to determine whether the diminished ovarian tissue seen in older girls and women reflects a failure of development, a regression of ovarian tissue over time, or a combination of both. The one documented case of apparently normal ovaries later becoming streak-like (Kaufman et al.
1981) suggested that the mechanism may be related to accumulated galactose ootoxicity over time.
Animal studies of galactose exposure reinforce the notion that the galactosemic ovary remains vulnerable to damage throughout life. The ovaries of genetically wild-type rats fed a high galactose diet exhibit decreased follicular development (Liu et al.
2006) and increased apoptosis of maturing follicles (Lai et al.
2003). In mice, preferential activation of the prolactin short-form receptor in the ovary, which represses
FOXO3 and subsequently inhibits GALT expression, results in accelerated follicular depletion and consequent ovarian failure (Halperin et al.
2008). These studies indicate that even in the absence of developmental damage to the ovary, later exposure to galactose or its metabolites may contribute to POI, both by suppressing normal follicular maturation and by increasing follicular death.
Recent reports that, at least in some galactosemic women, POI follows a fluctuating course (Gubbels et al.
2008,
2009) are also suggestive of multiple layers of galactose ootoxicity. These observations are also consistent with the apparently fluctuating course of POI in many women who do not have galactosemia (Van Kasteren and Schoemaker
1999). For these women, prohibition of primordial follicle maturation may be intermittently relieved by an as yet unknown mechanism, allowing for intervals of spontaneous ovulation, normal menstrual cycles, and fertility. Of note, one study of a small cohort of galactosemic women looked at spontaneous fertility outcomes (Gubbels et al.
2008) and reported that galactosemia patients with a diagnosis of POI may be more likely to conceive than women who have POI due to other causes. This possibility needs to be studied in a larger cohort because it may alter how galactosemic patients are counseled about their probability of conceiving.