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Galactose metabolism and ovarian toxicity
Reproductive Toxicology 14 (2000) 377–384
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Review
Galactose metabolism and ovarian toxicity Gentao Liu, Georgina E. Hale, Claude L. Hughes* Center for Women’s Health, Cedars-Sinai Burns and Allen Research Institute, Cedars-Sinai Medical Center/University of California Los Angeles, School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
Abstract Galactose is an energy-providing nutrient and also a necessary basic substrate for the biosynthesis of many macromolecules in the body. Metabolic pathways for galactose are important not only for the provision of these pathways but also for the prevention of galactose and galactose metabolite accumulation. Problems with galactose metabolism can cause a variety of clinical manifestations in animals and humans. It has been found that the mammalian ovary is particularly susceptible to damage from the accumulation of galactose and galactose metabolites. The galactose metabolites Gal-1-P, galactitol, and UDPgal are all considered to be important in this toxicity and proposed mechanisms include interference with ovarian apoptosis and gonadotrophin signaling. This review addresses the most recent scientific findings regarding the possible mechanisms of galactose-induced ovarian toxicity and also the possible protective role of hormonal and antioxidant therapy. In addition, the available epidemiologic and scientific evidence linking galactose intake with risk of ovarian cancer is discussed. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Ovary; Galactose; Metabolism; Pathogenesis of galactose; Prevention of galactose toxicity
1. Introduction In humans, ingested lactose is converted to glucose and galactose by the intestinal enzyme called lactase. The further metabolism of galactose to UDP-glucose involves three major enzymes, galactokinase, galactose-1-phosphate uridyltransferase (GALT), and UDP-galactose-4-epimerase. There are three clinically significant disorders of galactose metabolism, which are due to deficiencies of galactokinase, GALT, and UDP-galactose-4-epimerase [1]. The most common, however, is classic galactosemia, an autosomal recessive inherited deficiency of GALT. In the ovary, there is a relative abundance of these three enzymes [2], and this finding is thought to be related to the observation that women who have absent or low GALT activity have a propensity to develop premature ovarian failure and premature menopause [3–5]. The exact mechanisms of this ovarian failure in galactosemic females has not yet been fully elucidated but is currently under investigation. Further elucidation of these mechanisms will hopefully allow the development of new therapeutic options for galactosemic individuals and may also give us more information regarding * Corresponding author. Tel.: ⫹1-310-423-7432; fax: ⫹1-310-4230305. E-mail address: [email protected] (C.L. Hughes).
a possible association between galactose intake in nongalactosemic women and ovarian dysfunction. A number of epidemiologic studies have examined the relationship between intake of lactose from dairy products and ovarian cancer but, to date, the data remain conflicting.
2. Sources of galactose Galactose is ubiquitous in both animals and plants, where it is an important component of cell membrane lipids. Gross [6] and Acosta [7] also reported the presence of considerable amounts of free galactose in some fruits, vegetables, nuts, legumes, and beverages. In addition, foods fermented by microorganisms for preparation or preservation purposes may contain considerable amounts of free galactose. Despite significant amounts of galactose in foods such as figs, grapes, and split peas, dairy products remain the most common source of galactose in the diet. Human milk contains 5.5– 8.0% lactose by weight and cow milk, 4.5–5.5% [8]. The galactose content in some foods is shown in Table 1. Women in Western countries are urged to consume dairy products in order to increase their calcium intake and reduce the risk of osteoporosis [9,10]. As a result, intake of lactose can be substantial. Since lactose is a disaccharide and is hydrolyzed by lactase into glucose and galactose, galactose
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Table 1 The galactose content of some foods Food
Galactose content (mg/100 g)
Fruits Dried Figs Grapes, European
4100.0 400.0
Persimmon, American Papaya Watermelon Apple Banana Orange, sweet Vegetables Black-eyed peas Green peas, split Peas Tomato Pepper, bell Potato, sweet Nuts, seeds Hazelnuts, dried Safflower seed kernels Dairy products Milk (human) Milk (cow) Casein (whole) Cheddar cheese (aged 15 d) Beverages Coffee, dry Watermelon juice Orange juice Apple juice V-8 juice Legumes Navy beans Black turtle beans Great Northern beans Soybeans
35.4 28.6 14.7 8.3 9.2 4.3 521.0 493.0 161.0 23.0
glucose but glucose absorption is unaffected by galactose [14]. When galactose is absorbed along with glucose, serum galactose concentrations are considerably lower than when the same amount of galactose is consumed without glucose [15]. The absorption of galactose may also be reduced by leptin [17] and 3-adrenergic receptor agonists [16]. The pathways for galactose metabolism and associated enzyme reactions are shown in Fig. 1. The major pathway for galactose metabolism is considered to be the conversion of galactose to glucose by Gal-1-P, UDP-gal, and glucose-1-P. This conversion of galactose to glucose has been observed to be enhanced by glucose both via an increase in GALT activity in the liver and also via insulin action [18]. Aldose reductase also enhances the breakdown of galactose by catalyzing the NADPH-mediated conversion of galactose to galactitol. This pathway, however, is likely to be important in galactose toxicity via accumulation of galactitol.
10.2 7.7 500 100 5.5-8% lactose and 350 mg free galactose per 100 ml 4.5-5.5% lactose and 227 mg free galactose per 100 ml 134 94.5 1100 to 150 46 19 14 38 272 215 307 44
Source: Galactosemia Resources and information, website: http://www. miele-herndon.com/galactosemia/foods
intake may reach 5–20 g/day [11]. Humans also synthesize substantial quantities of galactose de novo from glucose and also from the reservoir of galactose within glycoproteins and mucopolysaccharides. This process is important for the maintenance of galactose and galactose metabolites needed for the synthesis of galactose-containing glycoproteins. On a galactose-restricted diet, endogenous galactose production ranges from 1.1 to 1.3 g/day [12].
3. Galactose absorption and metabolism Human studies have shown that galactose and glucose share a common intestinal transport carrier. This transport carrier has a greater affinity for glucose than galactose [13], which may explain why galactose absorption is inhibited by
4. Ovarian dysfunction in galactosemia Of the three clinically distinct inherited disorders of galactose metabolism, [1] GALT deficiency is the most common and is known as classic galactosemia. The clinical features of classic galactosemia are a result of the accumulation of intermediate galactose metabolites. The mammalian ovary is especially sensitive to these metabolites and germ cells, follicular (granulosa) cells, stromal cells, and thecal cells are all affected in galactosemia-related ovarian dysfunction [19 –21]. Ovarian dysfunction in galactosemia was first recognized in 1978 by Kaufman et al. [3] and Hoefnagel et al. [22] and confirmed by later studies [23–25]. Retrospective surveys suggest that up to 75–96% of all females who are homozygous for galactosemia have ovarian dysfunction [26,27]. Ovarian dysfunction is not reported, however, in females who are heterozygous for the condition [28,29]. The consequences of this ovarian dysfunction include failure of pubertal development, primary amenorrhea, secondary amenorrhea, and premature menopause. The gonadal dysfunction, which can occur at any age during the reproductive period [30,31], typically manifests in reduced ovarian gonadotrophin sensitivity and hypergonadotrophic hypogonadism [32]. The ovary’s susceptibility to galactose toxicity may in part be explained by unusually high local concentrations of enzymes responsible for the metabolism of galactose. Rogers et al. [33] and Heidenreich et al. [34] measured concentrations of GALT mRNA in various adult organs. They found GALT mRNA levels in organs from highest to lowest were liver ⬎ ovary ⬇ cerebellum ⬇ kidney ⬇ heart ⬎ cerebrum ⬎ lung ⬎ testis ⬎ skeletal muscle. Interestingly, these organs are affected in this order from greatest to least in patients with galactosemia. Not only are the concentrations of GALT and other galactose breakdown enzymes high in the ovary, the enzyme activities are also very high [2]. In addition, the activity of UDPglucose pyrophosphorylase is about 50 times that of GALT.
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Fig. 1. Galactose metabolism (2-4: major pathway; 5-6 minor pathway) 1 ⫽ lactase; 2 ⫽ galactokinase; 3 ⫽ galactose-1-phosphate uridyltransferase; 4 ⫽ UDP-4-epimerase; 5 ⫽ aldose reductase.
This high phosphorylase activity is likely to be important in the maintenance of germ cell function, maturation of follicles, and steroidogenesis since phosphorylase activity is important in nucleotide sugar production [2]. Any interference in this balance of galactose metabolism understandably could lead to germ and follicular cell dysfunction.
5. Animal models and galactose-induced ovarian toxicity Although studies in normal animal models fed excessive galactose-containing diets are not directly comparable to humans with enzyme deficiencies or normal individuals on varying galactose diets, important information about the mechanism of the ovarian toxicity has been uncovered. Rodent models have been used to study galactose toxicity and three basic feeding strategies have been employed. They are 1) pregnant animals were placed on high galactose diets during part or all of gestation to produce galactoseexposed fetuses, 2) prenatal exposure was continued into the
postnatal period by prolongation of the maternal diet, and 3) animals of various postgestational ages were placed on galactose-containing diets. Three important rodent studies are reviewed here. Chen et al. [35] demonstrated that female rat fetuses exposed to 50% galactose in the maternal diet during gestation have a significantly decreased number of oocytes. Swartz and Mattison [36] observed ovarian abnormalities in female adult mice fed a 40% galactose diet for only 2 weeks. These changes included inhibition of oocyte maturation shown by a decreased number of corpora lutea, an increase in interstitial tissue, and an increase in lipofuscin staining in the ovary, and a failure to respond to exogenous gonadotropins. Similar effects were reported by Meyer et al. [37] in prepubertal rats fed a high galactose diet. In this study, however, the ovarian abnormalities were observed to be lessened by an aldose reductase inhibitor. We studied Japanese quail, an animal model also widely used to study reproductive physiology and toxicology [38]. Our preliminary findings are consistent with those from the rodent model experiments. In quails fed a 10% galactose diet, there was a decrease in egg production and an increase
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in both mortality and mental depression. Given these findings, the quail may be another suitable animal model to experimentally address dietary and environmental factors in the etiology of galactose toxicity in women [39].
6. Mechanisms of galactose toxicity 6.1. Galactose metabolites The accumulation of galactose-1-phosphate (Gal-1-P) and galactitol and the deficiency of UDP-galactose are considered to be important in the pathogenesis of ovarian dysfunction and in GALT deficiency. Gal-1-P excess may contribute to toxicity in galactosemia by reducing energy availability through inhibition of several enzymes involved in glucose metabolism [40]. In high concentrations, Gal-1-P exerts an inhibitory effect on the enzymes of the phosphoglucomutase, glucose-6-phosphate dehydrogenase, pyrophorylase, and possibly glycogen phosphorylase pathways [41]. Gal-1-P competitively inhibits UDP-glucose pyrophosphorylase for which it is a substrate [42]. It has been found that UDP-galactose competes with UDP-glucose, although less effectively, for the same site on the enzyme. Immunologic evidence from experiments with galactosemia haemolysates supports this evidence [43]. In galactosemia, while GALT deficiency promotes accumulation of Gal-1-P, there is a concomitant need for UDP-galactose. The pyrophosphorylase pathway appears to have adequate capacity to convert glucose-1-P to UDP-galactose but not to convert Galactose-1-P to UDP-galactose [44]. Minimal GALT activity seems to be required to avoid accumulation of these intermediates since individuals with less than 1% of normal GALT activity (genetic variants) who have GALT activity and Gal-1-P levels similar to galactosemics, do not suffer from ovarian dysfunction [25]. The salient difference between classic galactosemics and these variants seems to be that the former is associated with a deficiency of UDPgalactose compared with UDP-glucose [45– 47]. UDP-galactose is needed for the synthesis of ovarian membrane glycoproteins and galactolipids [48], and it plays an important role in the support of germ cells, follicle maturation, and steroidogenesis [2]. Galactitol is metabolized poorly with poor cell membrane penetration. Galactitol accumulates in viable cells, which may cause osmotic imbalance and cellular swelling, which in turn may alter cellular ion permeability and result in cell dysfunction [37]. Galactitol has been shown to decrease the levels of glutathione in the ovary, which predispose to toxic levels of hydrogen peroxide [49]. The mammalian gonads appear to be especially sensitive to galactitol accumulation. In the rat model, it appears that females are more susceptible to this gonadal toxicity both because of higher serum galactitol concentrations (on the same diet as males) [50] and an increased sensitivity to galactose toxicity [51].
6.2. Alterations in gonadotropins and signaling In galactosemia, defects in gonadotropins or their receptors may influence ovarian toxicity since the expression of GALT is critical to normal ovarian development and function. Daude et al. observed that GALT expression was strongly correlated with gonadotropin synthesis in the rat pituitary and that GALT mRNA and protein were highly expressed during proestrus and estrus of the rat reproductive cycle [52]. Activation of FSH is dependent on glycosylation and seems to be altered during galactosemia. Prestoz [53] found that the terminal disaccharides on the FSH molecule, galactose and sialic acid, were partially deficient in galactosemic patients resulting in the formation of neutral isoforms. These isoforms of FSH were shown to have a higher binding affinity to the FSH receptor but little ability to activate it via cyclic adenosine monophosphate (cAMP). The investigators proposed that an increase in these isoforms could cause defects in gonadotrophin signaling and possibly act as antihormones, producing antagonistic effects at the FSH receptor. In another study, the biologic activity of FSH in galactosemic patients was found to be normal [23], however, these studies did not examine structural differences in the FSH molecule. 6.3. Effects on apoptosis The mechanisms regulating germ cell migration, proliferation of oogonia, and initiation of meiosis to form primordial follicles remain obscure. A perturbation in any of these complex processes could result in ovarian failure by reducing the initial follicle pool. Follicle atresia occurs by means of programmed cell death, known as apoptosis. Apoptosis accounts for the loss of at least 90% of the original oocyte number; 80% of this loss occurs before birth [54]. A number of factors rescue oocytes from apoptosis, including gonadotropins, estrogen, growth hormone, growth factors, cytokines, and nitric oxide [55]. Some factors promote oocyte apoptosis, such as tumor necrosis factor (TNF)-␣, Fas ligands, androgens, IL-6, and gonadal GnRH-like proteins [56]. Galactose may also play a role in follicular atresia by causing an accumulation of methyglyoxal through slowing of the glutathione redox cycle. This slowing of the redox cycle in turn promotes apoptosis [57]. Levy et al. published a single report of an autopsy in a galactosemic neonate where normal ovarian histology was found [31]. This finding in itself is inadequate evidence but implies that ovarian failure in patients with galactosemia is due to accelerating follicle atresia by apoptosis after birth. In keeping with this theory, Sato et al. demonstrated that galactose-induced apoptosis in dog retinal capillary pericytes could be partially prevented by aldose reductase inhibitors [58].
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6.4. Effects of galactose on immune function
7.2. Aldose reductase inhibitors
Abnormalities of the immune system may be responsible for ovarian dysfunction and primary ovarian failure [59]. The findings that support this link include an alteration of the number and ratio of the CD4 ⫹ and CD8⫹ T lymphocytes in patients with primary ovarian failure, a decrease in the number of NK cells in the sera of patients with primary ovarian failure [60], which is also seen in patients with Graves’ disease, and activation of the Fas-Fas ligand system (a cell-surface protein that can mediate programmed cell death in lymphoid cells and can induce apoptosis in granulosa cells) [61]. Galactosemic neonates have a high frequency of neonatal deaths due to fulminant Escherichia coli sepsis. This observation seems to be the only reported adverse clinical effect of galactose on the immune system, and, in 1971, Kelly suggested that this was due to a direct inhibition of galactose on leukocyte bacteriocidal activity [62]. There have been no subsequent studies to confirm or deny this theory.
Aldose reductase catalyses the NADPH-mediated conversion of galactose to galactitol. The affinity of aldose reductase for galactose is relatively low, and maximum rates of aldose reductase-catalysed formation of galactitol can be attained only with high intracellular concentrations of galactose as in galactosemia [70]. Aldose reductase inhibitors have been observed to cause reversal of galactose-induced toxicity in animals via a reduction in galactitol levels [71– 74]. Aldose reductase inhibitors have been found to prevent ovarian dysfunction in rats fed high galactose diets [37]. Other studies have shown that aldose reductase inhibitors can also inhibit mast cell degranulation [72] and Schwann cell injury [73]. In addition, in rats fed a high galactose diet, the aldose reductase inhibitor CT-112 has been shown to be effective in improving dysfunction of the corneal epithelial barrier [74].
7. Prevention of galactose-induced toxicity 7.1. Antioxidants Accumulation of galactitol in galactosemia impairs free radical scavenging by interfering with the glutathione reductase [63], which in turn reduces free radical protection. A similar process is observed in the lens, where accumulation of galactitol has been shown to cause early cataract formation [64]. In the rat lens, the rate of production of galactose related cataracts can be slowed with the administration of butylated hydroxytoluene, a free radical scavenger [65,66]. In addition, epidemiologic data indicate that elevated plasma levels of specific antioxidant nutrients (i.e. carotenoids, ascorbate, tocopherol, and taurine), can delay photograph-oxidative damage to lens proteins and have been associated with a diminished incidence of certain types of cataract [67]. In New Zealand white rabbits, taurine was found to protect against the development of galactose-induced cataracts, and Malone et al. found an inverse relationship between levels of lens malondialdehyde (an indicator of lipid peroxidation) and cataract [68]. It has also been reported that dietary ascorbate (ASC) delays the development of galactose-induced cataract in guinea pigs by decreasing polyol accumulation in the lens epithelium [69]. Consistent with this finding, galactitol accumulation in the lenses of dogs exposed to 30 mM galactose was significantly inhibited by the presence of either ASC or dehydroascorbate. Given these findings of the protective effect of antioxidants in galactose-induced lens abnormalities, it may be warranted to perform similar studies on the mammalian ovary. It may be feasible to administer antioxidant therapy to patients with galactosemia in an effort to minimize the ovarian damage.
7.3. Hormones Hepatic GALT activity is markedly increased by progesterone, as has been observed in the rat liver during pregnancy [75]. The administration of progesterone (2 mg/day) delayed the development of cataract in normal weanling rats fed a 30% galactose diet [76]. In keeping with this finding, GALT expression is maximal during the proestrus and estrus phases of the rat estrous cycle [52]. Diethystibestrol (DES) has also been observed to reduce galactose toxicity, and testosterone propionate has been observed to increase galactose toxicity in chicks [77]. Current therapy for galactosemia-associated ovarian failure consists of combined estrogen and progestin therapy, and, although the mechanism remains obscure, this treatment can result in the development of previously absent secondary sexual characteristics [21] and sometimes resumption of regular menstrual cycles [32].
8. Galactose and ovarian cancer risk Despite the fact that there are no data to indicate that ovarian cancer is more common in galactosemics, there has been interest among investigators as to whether galactose consumption is associated with ovarian dysfunction or ovarian cancer in nongalactosemic individuals. In a large demographic study, Cramer et al. found that populations with high milk consumption had lower fertility rates and a greater decline in fertility with age [78]. The same investigators observed an association between population frequency per capita milk consumption and ovarian cancer incidence in a study of 27 countries. They observed that women who had less GALT activity had a higher risk of ovarian cancer. When a ratio of lactose consumption to GALT (L/T) was calculated, cases had a mean L/T of 1.17 compared with 0.98 for controls, but this did not reach
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statistical significance [79]. Similarly, in Italy, investigators have found that lactase persistence (measured by hydrogen in the breath after a galactose challenge) was associated with risk of ovarian cancer [80]. In addition, evidence of a genetic link between GALT abnormalities and ovarian cancer was found in a case control study in Britain, where the N314D mutation, commonly associated with GALT abnormalities, was seen significantly more often in 206 ovarian cancer cases than in controls [81]. There have been some important studies that have found no association between either lactose or free galactose consumption and risk of ovarian cancer [82– 85]. In a case control study in Canada, Risch et al. studied 450 women diagnosed with epithelial ovarian cancer and found that neither a reported history of lactose intolerance, nor average daily consumption of lactose or free galactose were associated with risk of ovarian cancer [82]. Mettlin and Piver reported that an increased risk for ovarian cancer associated with milk consumption was confined to consumers of whole milk, rather than skim milk, and inferred from this finding the importance of animal fat rather than milk sugar (galactose) consumption [83]. Similarly, in a study of 800 cases in Australia by Webb et al. [84], ovarian cancer was positively associated with increasing consumption of whole-fat milk and full-fat dairy products but inversely associated with consumption of low-fat milk. Finally, in a case control study in Washington, Herrinton et al. studied 108 cases of ovarian cancer and found that neither lactose or free galactose intake were associated with an increased risk [85]. They also analyzed GALT activity and found erythrocytic GALT activity to be unrelated to ovarian cancer risk. Population dietary studies have a number of limitations related to the measurement of lactose and galactose intake using food frequency questionnaires administered retrospectively. In a study of U.S. men and women who completed two identical food frequency questionnaires 6 –10 years apart, the correlation between the first and second recall of dairy product intake was only 0.5 [86]. Interpretation of large population dietary studies must also include an adequate assessment of possible confounding factors. Although Cramer et al. [87] had previously found an association between dietary fat and ovarian cancer, in their later study [79], they did not perform a separate dairy fat analysis. That the fat content in dairy foods can confound the results of population studies such as these is illustrated by Webb et al. [84], who found that the consumption of full cream products but not skim milk products was associated with ovarian cancer. It is also conceivable that other “healthy” dietary and lifestyle factors associated with either low fat diary product intake or avoidance of dairy products could confound the results of such population dietary studies. All the studies by Cramer et al. [79,88], Cooper et al. [11], Webb et al. [84], and Herrington et al. [85] used erythrocytic GALT activity as a measure of ovarian GALT activity and ovarian function. The reliability, however, of
erythrocytic GALT activity as an accurate measure of ovarian GALT has been questioned by Xu et al. [2], who demonstrated markedly different electrophoretic patterns of erythrocytic GALT compared to hepatic and ovarian GALT. More specifically, Reichlin criticized the interpretation of GALT measurements in the study by Cramer et al. [79]. The estimates of erythrocytic GALT activity in ovarian cancer patients in this study were reported to be significantly lower than controls (P ⫽ 0.03) but the difference was so small as to be of doubtful biologic meaning (21.8 versus 22.8 mmol/h per g hemoglobin) [89]. 9. Conclusions In galactosemic individuals, despite the initiation of a lactose-free diet, long-term complications remain a problem. These problems include poor growth, speech abnormalities, mental deficiencies, neurologic syndromes, and ovarian failure in females. The significance of free and bound galactose in cereals, fruits, legumes, nuts, organ meats, seeds, and vegetables in galactosemic patients is unknown. The pathogenesis of the ovarian dysfunction in galactosemia and galactose-induced ovarian toxicity in the animal models is still unclear. It is likely that all three metabolites, galactitol, galactose-1-phosphate, and UDPgalactose, are important in the pathogenesis; however, our understanding of the molecular mechanisms involved remains inadequate. Aldose reductase inhibitors and antioxidants have been used with some success to reduce both lens and ovarian galactose toxicity in the animal model, but further investigation is warranted. In addition, although the mechanism has not been fully elucidated, both epidemiologic and scientific evidence in humans suggest at least a partial protective effect from the combined oral contraceptive pill. For nongalactosemic individuals, questions remain about the role of dietary galactose in ovarian cancer. From the data so far, the evidence against an association of galactose intake with ovarian cancer risk outweighs the evidence for it. Further animal studies on lactose versus galactose intake may help clarify whether there is any relationship between lactose intake and risk of galactose toxicity.
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[72] Brett FM, Kalichman MW, Calcutt NA, Mizisin AP. Effects of seven days of galactose feeding and aldose reductase inhibition on mast cells and vessel morphometry in rat sciatic nerve. J Neurol Sci 1996;141:6 –12. [73] Mizisin AP, Powell HC. Schwann cell changes induced as early as one week after galactose intoxication. Acta Neuropathol 1997;93: 611– 8. [74] Yokoi N, Niiya A, Komuro A, et al. Effects of aldose reductase inhibitor CT-112 on the corneal epithelial barrier of galactose-fed rats. Curr Eye Res 1997;16:595–9. [75] Segal S, Rogers S. Regulation of galactose metabolism: Implications for therapy. J Inherited Metab Dis 1990;13:487–500. [76] Pesch L, Segal S, Topper YJ. Progesterone effects on galactose metabolism in prepubertal patients with congenital galactosemia and in rats maintained on high galactose diets. J Clin Invest 1960;39:178 – 84. [77] Nordin JH, Wilken DR, Bretthauer RK, Hansen RG, Scott AM. A consideration of galactose toxicity in male and female chicks, Poultry Science 1960;39:802–12. [78] Cramer DW, Xu H, Sahi T. Adult hypolactasia, milk consumption and age-specific fertility. Am J Epidemiol 1994;139:282–9. [79] Cramer DW, Harlow BL, Willett WC, et al. Galactose consumption and metabolism in relation to the risk of ovarian cancer. Lancet 1989;2:66 –71. [80] Meloni GF, Colombo C, La Vecchia C, et al. Lactose absorption in patients with ovarian cancer. Am J Epidemiol 1999;150:183– 6. [81] Morland SJ, Jiang X, Hitchcock A, Thomas EJ, Campbell IG. Mutation of galactose-1-phosphate uridyl transferase and its association with ovarian cancer and endometriosis. Int J Cancer 1998;77:825–7. [82] Risch HA, Jain M, Marrett LD, Howe GR. Dietary lactose intake, lactose intolerance, and the risk of epithelial ovarian cancer in southern Ontario (Canada). Cancer Causes Control 1994;5:540 – 8. [83] Mettlin CJ, Piver MS. A case-control study of milk drinking and ovarian cancer risk. Am J Epidemiol 1990;132:871– 6. [84] Webb PM, Bain CJ, Purdie DM, Harvey PW, Green A. Milk consumption, galactose metabolism and ovarian cancer (Australia). Cancer Causes Control 1998;9:637– 44. [85] Herrinton LJ, Weiss NS, Beresford SA, et al. Lactose and galactose intake and metabolism in relation to the risk of epithelial ovarian cancer. Am J Epidemiol 1995;141:407–16. [86] Byers T, Marshall J, Anthony E, Fiedler R, Zielezny M. The reliability of dietary history from the distant past. Am J Epidemiol 1987; 125:999 –1011. [87] Cramer DW, Welch WR, Hutchison GB, Willett W, Scully RE. Dietary animal fat in relation to ovarian cancer risk. Obstet Gynecol 1984;63:833– 8. [88] Cramer DW, Muto MG, Reichardt JK, et al. Characteristics of women with a family history of ovarian cancer. I. Galactose consumption and metabolism. Cancer 1994;74:1309 –17. [89] Reichlin S. Galactose consumption and risk of ovarian cancer. Lancet 1989;2:565.
www.elsevier.com/locate/reprotox
Review
Galactose metabolism and ovarian toxicity Gentao Liu, Georgina E. Hale, Claude L. Hughes* Center for Women’s Health, Cedars-Sinai Burns and Allen Research Institute, Cedars-Sinai Medical Center/University of California Los Angeles, School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
Abstract Galactose is an energy-providing nutrient and also a necessary basic substrate for the biosynthesis of many macromolecules in the body. Metabolic pathways for galactose are important not only for the provision of these pathways but also for the prevention of galactose and galactose metabolite accumulation. Problems with galactose metabolism can cause a variety of clinical manifestations in animals and humans. It has been found that the mammalian ovary is particularly susceptible to damage from the accumulation of galactose and galactose metabolites. The galactose metabolites Gal-1-P, galactitol, and UDPgal are all considered to be important in this toxicity and proposed mechanisms include interference with ovarian apoptosis and gonadotrophin signaling. This review addresses the most recent scientific findings regarding the possible mechanisms of galactose-induced ovarian toxicity and also the possible protective role of hormonal and antioxidant therapy. In addition, the available epidemiologic and scientific evidence linking galactose intake with risk of ovarian cancer is discussed. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Ovary; Galactose; Metabolism; Pathogenesis of galactose; Prevention of galactose toxicity
1. Introduction In humans, ingested lactose is converted to glucose and galactose by the intestinal enzyme called lactase. The further metabolism of galactose to UDP-glucose involves three major enzymes, galactokinase, galactose-1-phosphate uridyltransferase (GALT), and UDP-galactose-4-epimerase. There are three clinically significant disorders of galactose metabolism, which are due to deficiencies of galactokinase, GALT, and UDP-galactose-4-epimerase [1]. The most common, however, is classic galactosemia, an autosomal recessive inherited deficiency of GALT. In the ovary, there is a relative abundance of these three enzymes [2], and this finding is thought to be related to the observation that women who have absent or low GALT activity have a propensity to develop premature ovarian failure and premature menopause [3–5]. The exact mechanisms of this ovarian failure in galactosemic females has not yet been fully elucidated but is currently under investigation. Further elucidation of these mechanisms will hopefully allow the development of new therapeutic options for galactosemic individuals and may also give us more information regarding * Corresponding author. Tel.: ⫹1-310-423-7432; fax: ⫹1-310-4230305. E-mail address: [email protected] (C.L. Hughes).
a possible association between galactose intake in nongalactosemic women and ovarian dysfunction. A number of epidemiologic studies have examined the relationship between intake of lactose from dairy products and ovarian cancer but, to date, the data remain conflicting.
2. Sources of galactose Galactose is ubiquitous in both animals and plants, where it is an important component of cell membrane lipids. Gross [6] and Acosta [7] also reported the presence of considerable amounts of free galactose in some fruits, vegetables, nuts, legumes, and beverages. In addition, foods fermented by microorganisms for preparation or preservation purposes may contain considerable amounts of free galactose. Despite significant amounts of galactose in foods such as figs, grapes, and split peas, dairy products remain the most common source of galactose in the diet. Human milk contains 5.5– 8.0% lactose by weight and cow milk, 4.5–5.5% [8]. The galactose content in some foods is shown in Table 1. Women in Western countries are urged to consume dairy products in order to increase their calcium intake and reduce the risk of osteoporosis [9,10]. As a result, intake of lactose can be substantial. Since lactose is a disaccharide and is hydrolyzed by lactase into glucose and galactose, galactose
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Table 1 The galactose content of some foods Food
Galactose content (mg/100 g)
Fruits Dried Figs Grapes, European
4100.0 400.0
Persimmon, American Papaya Watermelon Apple Banana Orange, sweet Vegetables Black-eyed peas Green peas, split Peas Tomato Pepper, bell Potato, sweet Nuts, seeds Hazelnuts, dried Safflower seed kernels Dairy products Milk (human) Milk (cow) Casein (whole) Cheddar cheese (aged 15 d) Beverages Coffee, dry Watermelon juice Orange juice Apple juice V-8 juice Legumes Navy beans Black turtle beans Great Northern beans Soybeans
35.4 28.6 14.7 8.3 9.2 4.3 521.0 493.0 161.0 23.0
glucose but glucose absorption is unaffected by galactose [14]. When galactose is absorbed along with glucose, serum galactose concentrations are considerably lower than when the same amount of galactose is consumed without glucose [15]. The absorption of galactose may also be reduced by leptin [17] and 3-adrenergic receptor agonists [16]. The pathways for galactose metabolism and associated enzyme reactions are shown in Fig. 1. The major pathway for galactose metabolism is considered to be the conversion of galactose to glucose by Gal-1-P, UDP-gal, and glucose-1-P. This conversion of galactose to glucose has been observed to be enhanced by glucose both via an increase in GALT activity in the liver and also via insulin action [18]. Aldose reductase also enhances the breakdown of galactose by catalyzing the NADPH-mediated conversion of galactose to galactitol. This pathway, however, is likely to be important in galactose toxicity via accumulation of galactitol.
10.2 7.7 500 100 5.5-8% lactose and 350 mg free galactose per 100 ml 4.5-5.5% lactose and 227 mg free galactose per 100 ml 134 94.5 1100 to 150 46 19 14 38 272 215 307 44
Source: Galactosemia Resources and information, website: http://www. miele-herndon.com/galactosemia/foods
intake may reach 5–20 g/day [11]. Humans also synthesize substantial quantities of galactose de novo from glucose and also from the reservoir of galactose within glycoproteins and mucopolysaccharides. This process is important for the maintenance of galactose and galactose metabolites needed for the synthesis of galactose-containing glycoproteins. On a galactose-restricted diet, endogenous galactose production ranges from 1.1 to 1.3 g/day [12].
3. Galactose absorption and metabolism Human studies have shown that galactose and glucose share a common intestinal transport carrier. This transport carrier has a greater affinity for glucose than galactose [13], which may explain why galactose absorption is inhibited by
4. Ovarian dysfunction in galactosemia Of the three clinically distinct inherited disorders of galactose metabolism, [1] GALT deficiency is the most common and is known as classic galactosemia. The clinical features of classic galactosemia are a result of the accumulation of intermediate galactose metabolites. The mammalian ovary is especially sensitive to these metabolites and germ cells, follicular (granulosa) cells, stromal cells, and thecal cells are all affected in galactosemia-related ovarian dysfunction [19 –21]. Ovarian dysfunction in galactosemia was first recognized in 1978 by Kaufman et al. [3] and Hoefnagel et al. [22] and confirmed by later studies [23–25]. Retrospective surveys suggest that up to 75–96% of all females who are homozygous for galactosemia have ovarian dysfunction [26,27]. Ovarian dysfunction is not reported, however, in females who are heterozygous for the condition [28,29]. The consequences of this ovarian dysfunction include failure of pubertal development, primary amenorrhea, secondary amenorrhea, and premature menopause. The gonadal dysfunction, which can occur at any age during the reproductive period [30,31], typically manifests in reduced ovarian gonadotrophin sensitivity and hypergonadotrophic hypogonadism [32]. The ovary’s susceptibility to galactose toxicity may in part be explained by unusually high local concentrations of enzymes responsible for the metabolism of galactose. Rogers et al. [33] and Heidenreich et al. [34] measured concentrations of GALT mRNA in various adult organs. They found GALT mRNA levels in organs from highest to lowest were liver ⬎ ovary ⬇ cerebellum ⬇ kidney ⬇ heart ⬎ cerebrum ⬎ lung ⬎ testis ⬎ skeletal muscle. Interestingly, these organs are affected in this order from greatest to least in patients with galactosemia. Not only are the concentrations of GALT and other galactose breakdown enzymes high in the ovary, the enzyme activities are also very high [2]. In addition, the activity of UDPglucose pyrophosphorylase is about 50 times that of GALT.
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Fig. 1. Galactose metabolism (2-4: major pathway; 5-6 minor pathway) 1 ⫽ lactase; 2 ⫽ galactokinase; 3 ⫽ galactose-1-phosphate uridyltransferase; 4 ⫽ UDP-4-epimerase; 5 ⫽ aldose reductase.
This high phosphorylase activity is likely to be important in the maintenance of germ cell function, maturation of follicles, and steroidogenesis since phosphorylase activity is important in nucleotide sugar production [2]. Any interference in this balance of galactose metabolism understandably could lead to germ and follicular cell dysfunction.
5. Animal models and galactose-induced ovarian toxicity Although studies in normal animal models fed excessive galactose-containing diets are not directly comparable to humans with enzyme deficiencies or normal individuals on varying galactose diets, important information about the mechanism of the ovarian toxicity has been uncovered. Rodent models have been used to study galactose toxicity and three basic feeding strategies have been employed. They are 1) pregnant animals were placed on high galactose diets during part or all of gestation to produce galactoseexposed fetuses, 2) prenatal exposure was continued into the
postnatal period by prolongation of the maternal diet, and 3) animals of various postgestational ages were placed on galactose-containing diets. Three important rodent studies are reviewed here. Chen et al. [35] demonstrated that female rat fetuses exposed to 50% galactose in the maternal diet during gestation have a significantly decreased number of oocytes. Swartz and Mattison [36] observed ovarian abnormalities in female adult mice fed a 40% galactose diet for only 2 weeks. These changes included inhibition of oocyte maturation shown by a decreased number of corpora lutea, an increase in interstitial tissue, and an increase in lipofuscin staining in the ovary, and a failure to respond to exogenous gonadotropins. Similar effects were reported by Meyer et al. [37] in prepubertal rats fed a high galactose diet. In this study, however, the ovarian abnormalities were observed to be lessened by an aldose reductase inhibitor. We studied Japanese quail, an animal model also widely used to study reproductive physiology and toxicology [38]. Our preliminary findings are consistent with those from the rodent model experiments. In quails fed a 10% galactose diet, there was a decrease in egg production and an increase
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in both mortality and mental depression. Given these findings, the quail may be another suitable animal model to experimentally address dietary and environmental factors in the etiology of galactose toxicity in women [39].
6. Mechanisms of galactose toxicity 6.1. Galactose metabolites The accumulation of galactose-1-phosphate (Gal-1-P) and galactitol and the deficiency of UDP-galactose are considered to be important in the pathogenesis of ovarian dysfunction and in GALT deficiency. Gal-1-P excess may contribute to toxicity in galactosemia by reducing energy availability through inhibition of several enzymes involved in glucose metabolism [40]. In high concentrations, Gal-1-P exerts an inhibitory effect on the enzymes of the phosphoglucomutase, glucose-6-phosphate dehydrogenase, pyrophorylase, and possibly glycogen phosphorylase pathways [41]. Gal-1-P competitively inhibits UDP-glucose pyrophosphorylase for which it is a substrate [42]. It has been found that UDP-galactose competes with UDP-glucose, although less effectively, for the same site on the enzyme. Immunologic evidence from experiments with galactosemia haemolysates supports this evidence [43]. In galactosemia, while GALT deficiency promotes accumulation of Gal-1-P, there is a concomitant need for UDP-galactose. The pyrophosphorylase pathway appears to have adequate capacity to convert glucose-1-P to UDP-galactose but not to convert Galactose-1-P to UDP-galactose [44]. Minimal GALT activity seems to be required to avoid accumulation of these intermediates since individuals with less than 1% of normal GALT activity (genetic variants) who have GALT activity and Gal-1-P levels similar to galactosemics, do not suffer from ovarian dysfunction [25]. The salient difference between classic galactosemics and these variants seems to be that the former is associated with a deficiency of UDPgalactose compared with UDP-glucose [45– 47]. UDP-galactose is needed for the synthesis of ovarian membrane glycoproteins and galactolipids [48], and it plays an important role in the support of germ cells, follicle maturation, and steroidogenesis [2]. Galactitol is metabolized poorly with poor cell membrane penetration. Galactitol accumulates in viable cells, which may cause osmotic imbalance and cellular swelling, which in turn may alter cellular ion permeability and result in cell dysfunction [37]. Galactitol has been shown to decrease the levels of glutathione in the ovary, which predispose to toxic levels of hydrogen peroxide [49]. The mammalian gonads appear to be especially sensitive to galactitol accumulation. In the rat model, it appears that females are more susceptible to this gonadal toxicity both because of higher serum galactitol concentrations (on the same diet as males) [50] and an increased sensitivity to galactose toxicity [51].
6.2. Alterations in gonadotropins and signaling In galactosemia, defects in gonadotropins or their receptors may influence ovarian toxicity since the expression of GALT is critical to normal ovarian development and function. Daude et al. observed that GALT expression was strongly correlated with gonadotropin synthesis in the rat pituitary and that GALT mRNA and protein were highly expressed during proestrus and estrus of the rat reproductive cycle [52]. Activation of FSH is dependent on glycosylation and seems to be altered during galactosemia. Prestoz [53] found that the terminal disaccharides on the FSH molecule, galactose and sialic acid, were partially deficient in galactosemic patients resulting in the formation of neutral isoforms. These isoforms of FSH were shown to have a higher binding affinity to the FSH receptor but little ability to activate it via cyclic adenosine monophosphate (cAMP). The investigators proposed that an increase in these isoforms could cause defects in gonadotrophin signaling and possibly act as antihormones, producing antagonistic effects at the FSH receptor. In another study, the biologic activity of FSH in galactosemic patients was found to be normal [23], however, these studies did not examine structural differences in the FSH molecule. 6.3. Effects on apoptosis The mechanisms regulating germ cell migration, proliferation of oogonia, and initiation of meiosis to form primordial follicles remain obscure. A perturbation in any of these complex processes could result in ovarian failure by reducing the initial follicle pool. Follicle atresia occurs by means of programmed cell death, known as apoptosis. Apoptosis accounts for the loss of at least 90% of the original oocyte number; 80% of this loss occurs before birth [54]. A number of factors rescue oocytes from apoptosis, including gonadotropins, estrogen, growth hormone, growth factors, cytokines, and nitric oxide [55]. Some factors promote oocyte apoptosis, such as tumor necrosis factor (TNF)-␣, Fas ligands, androgens, IL-6, and gonadal GnRH-like proteins [56]. Galactose may also play a role in follicular atresia by causing an accumulation of methyglyoxal through slowing of the glutathione redox cycle. This slowing of the redox cycle in turn promotes apoptosis [57]. Levy et al. published a single report of an autopsy in a galactosemic neonate where normal ovarian histology was found [31]. This finding in itself is inadequate evidence but implies that ovarian failure in patients with galactosemia is due to accelerating follicle atresia by apoptosis after birth. In keeping with this theory, Sato et al. demonstrated that galactose-induced apoptosis in dog retinal capillary pericytes could be partially prevented by aldose reductase inhibitors [58].
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6.4. Effects of galactose on immune function
7.2. Aldose reductase inhibitors
Abnormalities of the immune system may be responsible for ovarian dysfunction and primary ovarian failure [59]. The findings that support this link include an alteration of the number and ratio of the CD4 ⫹ and CD8⫹ T lymphocytes in patients with primary ovarian failure, a decrease in the number of NK cells in the sera of patients with primary ovarian failure [60], which is also seen in patients with Graves’ disease, and activation of the Fas-Fas ligand system (a cell-surface protein that can mediate programmed cell death in lymphoid cells and can induce apoptosis in granulosa cells) [61]. Galactosemic neonates have a high frequency of neonatal deaths due to fulminant Escherichia coli sepsis. This observation seems to be the only reported adverse clinical effect of galactose on the immune system, and, in 1971, Kelly suggested that this was due to a direct inhibition of galactose on leukocyte bacteriocidal activity [62]. There have been no subsequent studies to confirm or deny this theory.
Aldose reductase catalyses the NADPH-mediated conversion of galactose to galactitol. The affinity of aldose reductase for galactose is relatively low, and maximum rates of aldose reductase-catalysed formation of galactitol can be attained only with high intracellular concentrations of galactose as in galactosemia [70]. Aldose reductase inhibitors have been observed to cause reversal of galactose-induced toxicity in animals via a reduction in galactitol levels [71– 74]. Aldose reductase inhibitors have been found to prevent ovarian dysfunction in rats fed high galactose diets [37]. Other studies have shown that aldose reductase inhibitors can also inhibit mast cell degranulation [72] and Schwann cell injury [73]. In addition, in rats fed a high galactose diet, the aldose reductase inhibitor CT-112 has been shown to be effective in improving dysfunction of the corneal epithelial barrier [74].
7. Prevention of galactose-induced toxicity 7.1. Antioxidants Accumulation of galactitol in galactosemia impairs free radical scavenging by interfering with the glutathione reductase [63], which in turn reduces free radical protection. A similar process is observed in the lens, where accumulation of galactitol has been shown to cause early cataract formation [64]. In the rat lens, the rate of production of galactose related cataracts can be slowed with the administration of butylated hydroxytoluene, a free radical scavenger [65,66]. In addition, epidemiologic data indicate that elevated plasma levels of specific antioxidant nutrients (i.e. carotenoids, ascorbate, tocopherol, and taurine), can delay photograph-oxidative damage to lens proteins and have been associated with a diminished incidence of certain types of cataract [67]. In New Zealand white rabbits, taurine was found to protect against the development of galactose-induced cataracts, and Malone et al. found an inverse relationship between levels of lens malondialdehyde (an indicator of lipid peroxidation) and cataract [68]. It has also been reported that dietary ascorbate (ASC) delays the development of galactose-induced cataract in guinea pigs by decreasing polyol accumulation in the lens epithelium [69]. Consistent with this finding, galactitol accumulation in the lenses of dogs exposed to 30 mM galactose was significantly inhibited by the presence of either ASC or dehydroascorbate. Given these findings of the protective effect of antioxidants in galactose-induced lens abnormalities, it may be warranted to perform similar studies on the mammalian ovary. It may be feasible to administer antioxidant therapy to patients with galactosemia in an effort to minimize the ovarian damage.
7.3. Hormones Hepatic GALT activity is markedly increased by progesterone, as has been observed in the rat liver during pregnancy [75]. The administration of progesterone (2 mg/day) delayed the development of cataract in normal weanling rats fed a 30% galactose diet [76]. In keeping with this finding, GALT expression is maximal during the proestrus and estrus phases of the rat estrous cycle [52]. Diethystibestrol (DES) has also been observed to reduce galactose toxicity, and testosterone propionate has been observed to increase galactose toxicity in chicks [77]. Current therapy for galactosemia-associated ovarian failure consists of combined estrogen and progestin therapy, and, although the mechanism remains obscure, this treatment can result in the development of previously absent secondary sexual characteristics [21] and sometimes resumption of regular menstrual cycles [32].
8. Galactose and ovarian cancer risk Despite the fact that there are no data to indicate that ovarian cancer is more common in galactosemics, there has been interest among investigators as to whether galactose consumption is associated with ovarian dysfunction or ovarian cancer in nongalactosemic individuals. In a large demographic study, Cramer et al. found that populations with high milk consumption had lower fertility rates and a greater decline in fertility with age [78]. The same investigators observed an association between population frequency per capita milk consumption and ovarian cancer incidence in a study of 27 countries. They observed that women who had less GALT activity had a higher risk of ovarian cancer. When a ratio of lactose consumption to GALT (L/T) was calculated, cases had a mean L/T of 1.17 compared with 0.98 for controls, but this did not reach
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statistical significance [79]. Similarly, in Italy, investigators have found that lactase persistence (measured by hydrogen in the breath after a galactose challenge) was associated with risk of ovarian cancer [80]. In addition, evidence of a genetic link between GALT abnormalities and ovarian cancer was found in a case control study in Britain, where the N314D mutation, commonly associated with GALT abnormalities, was seen significantly more often in 206 ovarian cancer cases than in controls [81]. There have been some important studies that have found no association between either lactose or free galactose consumption and risk of ovarian cancer [82– 85]. In a case control study in Canada, Risch et al. studied 450 women diagnosed with epithelial ovarian cancer and found that neither a reported history of lactose intolerance, nor average daily consumption of lactose or free galactose were associated with risk of ovarian cancer [82]. Mettlin and Piver reported that an increased risk for ovarian cancer associated with milk consumption was confined to consumers of whole milk, rather than skim milk, and inferred from this finding the importance of animal fat rather than milk sugar (galactose) consumption [83]. Similarly, in a study of 800 cases in Australia by Webb et al. [84], ovarian cancer was positively associated with increasing consumption of whole-fat milk and full-fat dairy products but inversely associated with consumption of low-fat milk. Finally, in a case control study in Washington, Herrinton et al. studied 108 cases of ovarian cancer and found that neither lactose or free galactose intake were associated with an increased risk [85]. They also analyzed GALT activity and found erythrocytic GALT activity to be unrelated to ovarian cancer risk. Population dietary studies have a number of limitations related to the measurement of lactose and galactose intake using food frequency questionnaires administered retrospectively. In a study of U.S. men and women who completed two identical food frequency questionnaires 6 –10 years apart, the correlation between the first and second recall of dairy product intake was only 0.5 [86]. Interpretation of large population dietary studies must also include an adequate assessment of possible confounding factors. Although Cramer et al. [87] had previously found an association between dietary fat and ovarian cancer, in their later study [79], they did not perform a separate dairy fat analysis. That the fat content in dairy foods can confound the results of population studies such as these is illustrated by Webb et al. [84], who found that the consumption of full cream products but not skim milk products was associated with ovarian cancer. It is also conceivable that other “healthy” dietary and lifestyle factors associated with either low fat diary product intake or avoidance of dairy products could confound the results of such population dietary studies. All the studies by Cramer et al. [79,88], Cooper et al. [11], Webb et al. [84], and Herrington et al. [85] used erythrocytic GALT activity as a measure of ovarian GALT activity and ovarian function. The reliability, however, of
erythrocytic GALT activity as an accurate measure of ovarian GALT has been questioned by Xu et al. [2], who demonstrated markedly different electrophoretic patterns of erythrocytic GALT compared to hepatic and ovarian GALT. More specifically, Reichlin criticized the interpretation of GALT measurements in the study by Cramer et al. [79]. The estimates of erythrocytic GALT activity in ovarian cancer patients in this study were reported to be significantly lower than controls (P ⫽ 0.03) but the difference was so small as to be of doubtful biologic meaning (21.8 versus 22.8 mmol/h per g hemoglobin) [89]. 9. Conclusions In galactosemic individuals, despite the initiation of a lactose-free diet, long-term complications remain a problem. These problems include poor growth, speech abnormalities, mental deficiencies, neurologic syndromes, and ovarian failure in females. The significance of free and bound galactose in cereals, fruits, legumes, nuts, organ meats, seeds, and vegetables in galactosemic patients is unknown. The pathogenesis of the ovarian dysfunction in galactosemia and galactose-induced ovarian toxicity in the animal models is still unclear. It is likely that all three metabolites, galactitol, galactose-1-phosphate, and UDPgalactose, are important in the pathogenesis; however, our understanding of the molecular mechanisms involved remains inadequate. Aldose reductase inhibitors and antioxidants have been used with some success to reduce both lens and ovarian galactose toxicity in the animal model, but further investigation is warranted. In addition, although the mechanism has not been fully elucidated, both epidemiologic and scientific evidence in humans suggest at least a partial protective effect from the combined oral contraceptive pill. For nongalactosemic individuals, questions remain about the role of dietary galactose in ovarian cancer. From the data so far, the evidence against an association of galactose intake with ovarian cancer risk outweighs the evidence for it. Further animal studies on lactose versus galactose intake may help clarify whether there is any relationship between lactose intake and risk of galactose toxicity.
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