Compared to the placebo group, participants consuming the antioxidants plus zinc and copper showed a 28% reduction in progression to advanced AMD after five years. Subsequently, the AREDS2 was conducted with a newer formulation that included vitamins C and E, either 10 mg of L plus 2 mg of Z, and either 350 mg of docosahexaenoic acid plus 650 mg of eicosapentaenoic acid , or both. Patients were also given either 25 or 80 mg of zinc, each with 2 mg of copper. Beta-carotene was eliminated from the supplement due to a potential increased risk of lung cancer among smokers, who were already at high risk for AMD. Primary analyses of the AREDS2 formula found no additional benefit in reducing progression to advanced AMD, in comparison to the original AREDS formula. However, in a secondary analysis of combined data from AREDS and AREDS2, the progression risk in those receiving L and Z was significantly lower than in other groups. Neither formulation reduced the progression from early to intermediate AMD. These clinical trials did not monitor the MPOD status over time, thus limiting our understanding of the link between L and Z intake, retinal accumulation, and AMD development or progression. To date, dutch buckets the AREDS2 formula remains the standard of care for management of patients with intermediate AMD.The accumulation of L and Z in the macula starts in utero in primates and plays a critical role in visual development and maturation later in life.
Lutein and Z were detected as early as 20 weeks of gestation in macular tissue from human fetuses inspected at autopsy. Unlike fully matured human eyes, L is the dominant macular pigment in infants under the age of two regardless of eccentricities. The retina is less mature at birth compared to other eye structures, with complete differentiation requiring four to five years. The maturation of the macula is associated with a change in the L:Z ratio over the first four years of life, which correlates with the development of cone photoreceptors. Studies in premature infants illustrate the importance of these L and Z in visual development. In preterm human neonates, extremely low levels of serum L and Z are associated with an undetectable MPOD.79 When a carotenoid-fortified formula containing 211 µg/L of combined L and Z was given to preterm infants, plasma carotenoid levels became comparable to breastfed preterm infants, and were significantly higher than those fed formulas without L or Z fortification. In a small study that monitored the concentration of L and Z in various infant formulas and breast milk from different mothers, Z was not detected in any formula but was present in all breast milk samples, while L was consistently higher in breast milk. Serum L was also noted to be six-fold higher in breastfed infants compared to those fed with a formula devoid of L. Further studies are warranted to assess the prospective effects of L- and Z-fortified formula on MPOD and visual development in infants as they enter adulthood. Lutein and Z may also protect against oxidative damage in premature infants, especially those with retinopathy of prematurity . Premature infants with ROP usually have poor visual acuity, even after laser treatment or intravitreal injection of anti-vascular endothelial growth factor agents.
In a model of oxygen-induced retinopathy, mouse pups given L showed less vessel leakage and lower avascular area compared to those given a L-free control. The authors suggested that the anti-oxidant properties of L may have contributed to these results, although ROS levels were not measured. Studies that investigate L and Z supplementation in ROP babies have produced inconsistent results. In a multi-center, double-blind, randomized controlled trial of very-low-birth-weight infants, no difference was found in the incidence of ROP between those supplemented with daily oral L and Z or placebo. However, the progression rate of threshold ROP showed a lower trend in the supplemented group. No adverse events were noted with L and Z supplementation, suggesting that they were well-tolerated. Another study examining the effects of daily oral L and Z supplementation in preterm infants from the seventh day after birth until 40 weeks of age or until hospital discharge found no change in the rate or severity of ROP compared to placebo. Further, a meta-analysis of three randomized controlled trials also found no protective association between L and Z supplementation and the risk of ROP. Additional studies are needed to assess the role of prenatal L and Z supplementation in pregnant women at risk for premature delivery.During development, L and Z are not interchangeable. Serum Z in newborns and in their mothers is strongly correlated with the MPOD of the babies, but no relationship was noted for either maternal or infant levels of L.
During delivery, a high maternal plasma Z, but not plasma L, was significantly associated with a lower risk of visual acuity problems in children at three years of age. Further investigations that can accurately distinguish and quantify dietary and plasma Z from L are needed to better understand the role of these two carotenoids in visual performance during development. The L and Z in human milk is particularly important for infant eye and brain development, and may provide long term benefits to vision and cognition. Since humans cannot synthesize carotenoids, the fetus and breastfed infants must obtain these compounds from the mother through the placenta and the breast milk. During gestation, maternal lipoprotein synthesis increases, which accelerates the transport of carotenoids to the fetus. This transfer may deplete maternal stores if the dietary intake of carotenoids in general, and L and Z specifically, is inadequate to maintain body stores. Low maternal skin and serum carotenoid levels have been reported in mothers of newborn infants. The prevalence of AMD is higher in women than in men, even though on a global basis more men smoke. At the same time MPOD levels are lower in females. The potential reasons for an increased lifetime risk for AMD in women are complex and multi-factorial in nature and may include maternal depletion of L and Z during pregnancy and lactation . Importantly, the average dietary consumption of L and Z among females in the US is far below the amount of 10 mg/d known to increase MPOD. Therefore, either the intake of supplements containing L and Z, or increased intake of foods rich in these two carotenoids for the duration of pregnancy and lactation may be of value.The concentration of β-carotene, lycopene, L and Z, the main carotenoids in breast milk are associated with maternal dietary intake over the first six months of lactation. Daily maternal supplementation of either 6 mg of L with 96 µg of Z, or 12 mg of L with 192 µg of Z, over six weeks resulted in a dose-dependent increase in L and Z levels in the breast milk and of the mothers and their infants when assessed three to four months postpartum. Another study reported that more carotenes were present than xanthophylls in maternal plasma, whereas more xanthophylls such as L and Z were presented in breast milk, in comparison to carotenes. These findings support the notion that maternal-infant transfer of carotenoids may occur, possibly at the expense of the mother. Future studies are needed to clarify if breastfeeding or L and Z intake may impact their AMD risk. The L-ZIP supplementation trial is currently exploring whether prenatal supplementation of 10 mg of L and 2 mg of Z will maintain maternal body stores, prevent potential macular pigment depletion during pregnancy, or enhance systemic and ocular carotenoid stores for both mothers and infants. Clinical trials on the long-term effects of perinatal L and Z intake on MPOD changes among mothers and infants are also warranted.100 Unfortunately, longitudinal studies on AMD in females often do not include breast-feeding history. A useful study design would be to investigate MPOD levels and relative risks of AMD between multiparous and nulliparous women, and in mothers practicing breastfeeding compared to formula feeding. Dietary intake of L and Z would be important to assess. Recognizing that such a study would take decades, shorter term studies could be conducted in non-human primates. Another challenge in retrospective studies is that breastfeeding history may not be accurate. Therefore, studies on the maternal transfer of L and Z during pregnancy and lactation with MPOD changes in infants and throughout the lifespan, grow bucket could be important but difficult to conduct. Future research should also focus on the measurement of L and Z status and MPOD in mother-infant pairs of twins or short birth intervals. Last, when accessing AMD risk in women, reproductive hormone status may be a confounding factor.
Estrogen has been shown to reduce oxidative stress and inflammation in RPE cells as well as systemically. Lifetime estrogen exposure such as the number of pregnancies, menopause, reproductive period, oral contraceptive use, and hormone replacement therapy may all influence the risk of developing AMD. Current evidence regarding estrogen exposure and risk of AMD is inconsistent. One study reported that postmenopausal hormone use decreased the risk of neovascular AMD but increased the risk of early AMD, while parous women showed a reduced risk of early AMD but not neovascular AMD. Two nationwide studies from South Korea among postmenopausal women noted that exogenous estrogen exposure was not a protective factor for AMD. A cohort study found that hormone replacement therapy and a longer reproductive period was associated with an increased risk of neovascular AMD. A cross sectional study showed that oral contraceptive use was associated with an increased risk of late AMD.106 In addition, a review summarizing the effect of estrogen exposure and the risk of all age-related eye diseases concluded that HRT, or the use of oral contraceptives, could be either positively or negatively associated with the risk of AMD.103 In contrast, some studies have reported that a longer duration of breastfeeding may be protective from late but not early AMD, even when the estrogen level was low during lactation. Future studies on the interaction of different reproductive and estrogen exposure histories and AMD risk are needed.Humans cannot synthesize carotenoids, and the best dietary sources are fruits, vegetables, egg yolks, and dairy products. Consuming a diet rich in green leafy vegetables and fish is recommended by the National Eye Institute for the high carotenoid and DHA and EPA contents. Nevertheless, in the carotenoid group, L and Z are not yet considered essential, or even conditionally essential, so no dietary reference intakes for these two compounds exists. The US intake of L and Z has been decreasing. According to the U.S. National Health and Nutrition Examination Survey , the average intakes of L plus Z were 2.15 mg/d in males and 2.21 mg/d in females in 1987, and 2.15 mg/d in males and 1.86 mg/d in females in 1992. In NHANES 2013-2014, the average intakes of L and Z in males and females was 1.58 mg/d and 1.76 mg/d, respectively. Moreover, based on data from NHANES 2003-2004, the reported intake of L was significantly higher than Z in all age groups and ethnicities. Importantly, the Z to L ratio was also lower in females than males older than 31 years of age, which may result in a higher risk of AMD in women than in men. However, due to difficulties in analyzing dietary L and Z separately, most studies analyze both carotenoids together. Since the amount of L in most foods is significantly greater than Z, precise quantification of Z has been a challenge. The amount of L and Z in foods and dietary supplements appears to be safe.112 No adverse events were found in clinical trials giving L at 30 mg/d for 120 days or 40 mg/d for 63 days. The only reported adverse effect after a daily supplementation of 15 mg L in a 20-week trial was a single case of self-reported carotenodermia, a reversible condition of orange skin color. Although a higher amount has been used in human studies, after assessing the potential risks, the observed upper safety level for L has been proposed as 20 mg/d. The European Food Safety Authority concluded safe upper limits for L and Z for use in dietary supplements were 1 mg/kg body weight/d and 0.75 mg/kg body weight/d, respectively. In primate models, rhesus monkeys fed a xanthophyll-free diet for 3 to 6.5 years developed extremely deficient or absent macular yellow pigment and drusen-like bodies.