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The presence of hormones in milk and dairy foods was discussed decades ago but rather more concerns attended to that with respect to finding hormones as biomarkers in milk for diseases and pregnancy diagnosis.
Moreover, considerable amount of studies demonstrated that existing of hormones in humans and animals milk are essential for infants growing and immunity. During the last couple of years, increasing body of evidence are indicating another property of hormones in dairy products as possible impact on human health including the role of some estrogens and insulin-like growth factor-1 in initiation and provoking of breast, prostate and endometrial tumours.
We put no limitation on date of published date. Moreover, our own published and conducted methods and results also are presented. The collected data from other researchers and our own data are indicating that the presence of steroid hormones in dairy products could be counted as an important risk factor for various cancers in humans. Our gathered data in this review paper may suggest more sophisticate analytical detection methods for oestrogens determination and also could be considered as a remarkable concern for consumers, producers and public health authorities.
Providing consumer information about the relationship between diet and health over the last decade has been raised and consequently elevated the awareness and demand for functional food ingredients. Milk or dairy products such as cheese, butter, and yoghurt are the most important components of human diet especially in the Western culture and recently in Asia. It is well known apart from dairy foods basic nutritional role many of them contain a number of hormones, which they have capability to mediate specific physiological and pathological functions 1.
Moreover, the presence of hormones in dairy products that have the potential to disrupt the physiological function of endocrine systems has raised great concern worldwide 2.
Any subtle changes in endocrine function may alter the growth, development, and reproduction in exposed animals and humans. The most important hormones found in milk and other dairy products by using a variety of analytical methods consist of prolactin, steroids including estrogens, progesterone, corticoids, and androgens.
Moreover, the existence of other hormones such as insulin-like growth factor-1 IGF-1 3 and local hormones including prostaglandins PGs 4 , 5 , in dairy products has been reported.
It has been assumed that most of the hormones are transferred into milk by diffusion. However, evidence is available for active mechanisms like those for progesterone in goats and prolactin in cows 6 , 7.
PGs level in milk samples could be used as a marker of mastitis in cows 8. The naturally occurring hormones in dairy foods have biological effects in humans and animals, which are ranging from growth promoting effects that related to sex steroids 9 , to carcinogenic properties that associate to some active metabolites of oestrogens and IGF-1 However, when a hormone or its metabolite is evaluated as a potential hazard for humans and animals, a few critical points should be clarified.
In first step, determining of accurate amounts of free and bound forms of naturally occurring hormones in dairy foods must be conducted. Secondly, it should be clarified that how percentage of determined hormones are absorbed via gastrointestinal tract and consequently, how percentage of absorbed hormones undergo hepatic biotransformation, which at the end will provide a clear picture of bioavailability for each individual hormones.
Performing in parallel some in vivo and in vitro toxicological studies to prove the potential biological effects including beneficial or detrimental effects of proposed hormones at the same levels, which are present in circulation system, will be the final step of this evaluation.
Prolactin PRL , is a polypeptide hormone, which is found in milk of several species including cows, sheep, goats, saws, rats, and humans In lactation period, PRL is released from the anterior pituitary gland in response to milking stimuli and suckling. Moreover, the couplomimetic stimulus to the cervix during coitus are also classified as physiological stimuli for PRL release The secretion of PRL is not limited to the anterior pituitary gland as some other organs and tissues such as hypothalamus, telencephalon, hippocampus, amygdala, septum, brain stem, and spinal cord, showed capability of PRL synthesis in animal studies 13 , Experimental studies demonstrated that subcutaneously injection of PRL in rat resulted in selectively accumulation in milk gland In contrast to other hormones, which are endocytosed and then immediately degraded in lysosomes, PRL is transported into the mammary epithelial cells by transcytosis and consequently released in the milk either in intact or cleaved forms The highest concentration of PRL were found in the milk of cows and women during the first days after parturition 6.
In cows, there is no significant difference in PRL content of the milk between different milking. In contrast, season dose have a strong influence on PRL concentration, as the highest concentrations of PRL were found during July and the lowest levels obtained during November 6.
The best-established sites of PRL action in mammals include the mammary gland and ovaries, however, PRL binding sites have been identified in other parts of the body such as CNS, pituitary gland, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle and skin The Lactogenesis, regulation of ovarian and testicular functions, contribution in reproductive and parental behaviours, angiogenesis, home-ostasis of the immune system and osmoregulation are the well-known functions of the PRL It seems, for adults of all species, the PRL in consumed milk is more likely hydrolysed to its constituent amino acids before absorption 6.
Thus, it is thought at least for adults, existing of high or low levels of PRL in consumed milk do not have biological impact. However, other studies demonstrated that milk PRL is absorbed and exert biologically effects including differentiation and maturation of neonatal neuroendocrine, regulation of the reproductive and immune systems in the neonates Moreover, it is indeed demonstrated there were positive correlations between PRL concentration in plasma and increasing saturated fatty acid intake and by contrast, negative relationship between PRL concentration in plasma and vitamin C level of the diet Jonhansson and co-workers have shown that the level of milk prolactin was lower when cows were fed before and after than during milking IGF-1 is a 70 amino acid-linked polypeptide produced mainly by mammary gland and liver 24 , but in general by all tissues and can act as an endocrine as well as paracrine and or autocrine fashion The broad area between minimum and maximum concentrations of IGF-1 in caws, milk could be due to differences in body weight, milk composition, diet, management practices, and other environmental factors.
Since treatment of lactating cows with bovine somatotropin showed significant increase of milk IGF-1 concentration No significant relationship between IGF-1 level in milk and milk production was reported. However, concentration of milk IGF-1 dramatically dropped during the lactation period as 6. As milk IGF-1 is not destroyed by milk processing especially pasteurisation, thus it will be present in shelf milk, too 3. Data about the bioavailability of milk IGF-1 in animals and humans is lacking and it is not clear yet, how percentage of IGF-1 in consumed dairy products could be reached through the gastrointestinal tract into central compartment since it is structurally more similar to the insulin, which is rapidly degraded in gut.
However, obvious beneficial effects of the milk- and more importantly colostrums IGF-1 in neonates indicates a higher absorption and less degradation of milk IGF-1 in milk-consumer neonates in comparison to the neonates, which are received milk replacer with lack of IGF-1 The physiological role of IGF-1 on glucose metabolism and growth was demonstrated early in the s IGF-1 like as insulin play a central role in cellular glucose metabolism, amino acid uptake, glycogen synthesis, lipogenesis, and mitogenesis IGF-1 receptor is a member of the tyrosine kinase family, which following binding to agonist compounds IGF-1 , causes autophosphorylation of tyrosine residues in the carboxyl end of the intracellular domain and eventually leads to a cellular response At the same time, the anabolic signals by IGF-1 or insulin can promote tumour development by anti-apoptosis effect and also by stimulating cell proliferation During the last years according to the epidemiological evidence accuracy of the hypothesis is promoting, which indicates the risk of the colon, pancreas, endometrium, breast and prostate tumours are associated to the high level of IGF-1, insulin, or both For example, PGI 2 is a major prostaglandin product in gastrointestinal tract and play a crucial role in the cytoprotection of gastric mucosal surface At the same time it is shown that PGI 2 dose have protective property in cardiomycytes against oxidative stress, as well Regardless to the bioavailability of the dairy products PGs following oral consumption, due to protective effects of them in gastric ulcer, beneficial property of them in human diet in normal level positively is considerable.
However, due to the rapid metabolic degradation of PGs, it is far unlikely that dairy foods PGs exert considerable systemic biological effects because these compounds are degraded in the liver by oxidation at the site of carbon 15 and producing of ketoprostaglandins, which are biologically inactive metabolites On the other hand, high level of PGs in dairy foods especially in milk could be considered as a marker for bacterial mastitis and other inflammations Glucocorticoids GCs are another group of hormones in dairy foods especially milk, which act synergistically with other hormones in lactogenesis.
Endogenous glucocorticoids are mainly synthesised in the adrenal gland and both synthesis and release of them are controlled by the adrenocorticotrophic hormone ACTH. Among the others, cortisol as the predominant glucocorticoid, is taken up from blood by the mammary glands of goats and cows 41 , The normal concentration of total GCs 0.
GCs are located mainly in the non-lipid fraction of the milk 6. Table 1 shows the concentrations of main hormones in cows, milk. It is found that due to widespread utilize of dexamethasone as a synthetic glucorticoid, in veterinary medicine, for treatment of metabolic diseases in ruminants, e. Moreover, another study showed that following treatment of the lactating Holstein cows by adrenocorticotropin hormone the milk cortisol level increased four-fold and that increase was due to sustained increase in plasma corisol level At the same time, stressful conditions such as transport, neuronal diseases, diet changes, environmental alteration including temperature changes and hundreds other stress producing factors might elevate the levels of GCs in milk.
Despite all the progress in terms of detection and quantification of GCs in milk, there is lack of knowledge about the possible absorption and consequently biological effects of milk GCs in animals and humans. GCs are comprehensively metabolised oxidation, reduction, and hydroxylation in the liver and the conjugated glucoronidated or sulfatated forms of the metabolites are excreted mainly via the urine and the bile depending on the species.
Since two decades ago a number of different analytical methods have been developed to detect and quantify the concentrations of naturally occurring and synthetic GCs in dairy products particularly in milk.
Very early studies for detection and quantification of GCs have been performed using comparative protein binding CPB method 43 , and radioimmunoassay technique Recently, liquid chromatography- mass spectrometry LC-MS techniques have been developed for quantitative determination of synthetic GCs in bovine milk Another study figured out that anderstanedion concentrations of plasma and milk were increased during pregnancy but the rate of elevation in milk was determined as twice as plasma after day 90 Until now, no more data is available on new analytical techniques, on minimum- biological-effects-producing levels, on diversity of androgens level in different dairy food, and on oral bioavailability of the androgens.
However, very early studies postulated that the measured naturally occurring androgens in milk unlikely could posse the biological effects in milk consumers 6. Progesterone and dihydroprogestrones are largely produced in ovaries and placenta. Progesterone is one of the essential hormones in the whole processes of animals and humans reproduction from ovulation to the maintenance of the pregnancy, development of mammary glands and neurobehavioral roles associated with sexual responsiveness 57 , Progesterone was detected and measured in milk of different species of animals but for the first time in cows, milk and due to highly non-polarity property it is mostly distributed within the fat fraction of milk Progesterone presence in milk or in a correct term an increase in milk Progesterone concentration has been used as a good diagnostic tool in pregnancy confirming in veterinary medicine The physiologic concentrations of Progesterone in cows, milk at different reproductive status of oestrus, day 21 of cycle, midcycle, and pregnancy were determined as 5.
The measurable level of P in dairy foods and commercial milk products by using radioimmunoassay was 1. This investigation confirmed again the high lipophylicity of progesterone Other studies also demonstrated the differences between progesterone concentrations in milk and milk products Table 2. The kinetics studies of Progesterone transfer from blood into milk show that the pathways of trans-cellular, simple and facilitate diffusion are involved However, involvement of hydroxysteroid dehydrogenases, in biotransformation of the progesterone has also been demonstrated.
Moreover, it has been also shown that this increase could exert proposed progestational response in target tissues There is lack of knowledge about the kinetics of Progesterone and its potentially active metabolites in human following consuming of dairy foods in particular fatty foods butter which contain high amounts of progesterone.
The milk Progesterone concentration was lowered in cows, which fed by high level of concentrate and the possible interpretation for that reduction was a consequence of increased metabolic clearance of progesterone associated with increased energy intake.
It has been found that the milk-cumulative progesterone concentration during the third luteal phase postpartum was higher for cows with low milk yields Estrogens play a critical role in most metabolic, behavioural and morphological requirements, which are essential in reproduction of the female vertebrates. There is no doubt that estrogens govern important activities including metabolic reactions in male, too During the last decades huge amount of studies have been performed to screen the presence of exohormones in human environment, which these efforts have led to increasing concern about their impact on wildlife and human health In contrast, there is lack of knowledge about possible exposure to endogenous sex steroids from food, about precise measurement methods, about the possible impact of naturally occurring steroid hormones and their metabolites on human and animal health and so on.
It is known that steroid hormones naturally occurring either in animals such as beef and veal because of their misuse as anabolic agents 73 and in non-treated cattle Thus, estrogens are unavoidable hormones in non-vegetarian human nutrition. Recent epidemiological studies indicating a very strong relation between milk and dairy products high consumption and high incidence of testicular and prostate cancers In the following pages of current review the estrogens and their metabolites content of human diets with especial emphasis on milk and dairy products is summarized.
Moreover, the possible impact of milk and dairy products estrogens on human health along with analytical methods of estrogens quantification are discussed. Since, nowadays use of more vegetal flours, which are known to contain high amounts of phytoestrogens including isoflavones in animal feeds, is usual, then it could create a great concern about the possible transfer of these compounds from the bovine feed to the milk and finally to human food chain Plant isoflavonoids especially in soybean products and other legumes are converted by intestinal bacteria to hormone-like compounds with estrogenic activity Naturally occurring of steroid hormones in animals has been frequently reported.