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, grow bucket 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. 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 multifactorial 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 breastmilk 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 multi-parous 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, 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. The pathogenesis of AMD involves oxidative stress and immune dysregulation.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,106,107 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, dutch bucket for tomatoes 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. 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. When 3.9 µmol/kg per day of L or Z for 24 to 101 weeks were supplemented, the rhesus monkeys showed significant increases in their corresponding serum, retinal, and adipose tissue concentrations. In their retina samples, L and meso-Z, but not Z, appeared in the L-supplemented group, while only Z was found in the group supplemented with Z. In humans, a study investigating the serum and macular responses of L, Z, and meso-Z from dietary supplements found that 13.13 mg/d for 12 weeks provided maximum MPOD improvement, whereas 7.44 mg/d was the amount that increased serum levels at the highest efficacy. These and other studies support the need for dietary recommendations for L and Z, particularly as conditionally essential nutrients due to their protective effects on eye health. Lutein and Z fulfill many criteria as essential nutrients, including high concentrations in select tissues, biological plausibility for eye health, depletion outcomes such as vision impairment in primates, and inverse associations with certain diseases. In addition to their role in eye health, L and Z are involved in cognitive function at all stages of life. A randomized controlled trial reported that L and Z supplementation improved neural efficiency and learning performance by increasing the interaction of numerous brain regions in older adults. Other reports have demonstrated an association between L intake or circulating levels and preserving age-related cognitive decline, reducing the risks of certain cancers, coronary heart disease, stroke, metabolic syndrome, and achieving higher levels of physical activity. A systematic review of in vivo, ex vivo, and in vitro studies concluded that L may benefit vascular health by improving endothelial function, reducing inflammation, regulating favorable lipid profiles, and maintaining glucose homeostasis. Systematic reviews summarizing the amount of L needed for cognitive functions and enhancement of gray matter volume estimated that at least 10 mg/d for 12 months could be beneficial. Age must be considered when creating DRI values, since MPOD values are lower in older compared to younger individuals. Whether the proposed intake of L and Z should be based on the amount that can reduce AMD risk, benefit visual maturation in newborns, protect cognitive health, or reduce the risk of other diseases requires further consideration. Sex differences in AMD prevalence must also be considered, especially in relation to pregnancy and lactation, as discussed above. Nevertheless, L and Z are not included for DRI consideration due to inadequate details from food databases, limited large-scale dietary intake studies, and insufficient knowledge regarding their metabolism and biological functions. Many continue to advocate for a DRI for L, since it satisfies all nine criteria for bio-active compounds. A rich dietary source of L and Z is goji berry, also called wolf berry or Gou Qi Zi. The bright orange-red colored oval fruit, has been used for millennia in traditional Chinese medicine for its role in visual health, to provide immunoregulatory, neuro-protective, and anti-inflammatory benefits, and to help regulate liver and kidney meridians . Commercially-available goji berries and their products come primarily from the Ningxia and Xinjiang autonomous regions in western China. Goji berry is known for its high amount of carotenoids, with the Z content higher than any other known food. In addition to carotenoids, other bioactive compounds found in goji berries include Lycium barbarum polysaccharides , flavonoids, vitamins, minerals, betaine, cerebrosides, phenolic acids, and certain amino acids which may also support the overall health of the eye, particularly when working synergistically.