Pesticides in human milk of Western Australian women and their influence on infant growth outcomes: A cross-sectional study.

Persistent organic pollutants in human milk (HM) at high levels are considered to be detrimental to the breastfed infant. To determine the pesticide concentration in HM, a pilot cross-sectional study of 40 Western Australian (WA) women was carried out. Gas chromatography-tandem mass spectrometry (GC-MS/MS) with a validated QuEChERS was used for the analysis of 88 pesticides in HM. p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) with a mean concentration of 62.8 ± 54.5 ng/g fat was found, whereas other organochlorines, organophosphates, carbamates and pyrethroids were not detected in HM. Overall, no association was observed between HM p,p'-DDE concentrations and maternal age, parity, body mass index and percentage fat mass. Furthermore, for the first time no significant association was found between p,p'-DDE concentrations in HM and infant growth outcomes such as weight, length, head circumference and percentage fat mass. The calculated daily intake was significantly different to the estimated daily intake of total DDTs and was well below the guideline proposed by WHO. The DDTs levels in WA have also significantly decreased by 42 - fold since the 1970s and are currently the lowest in Australia.

Human milk miRNAs primarily originate from the mammary gland resulting in unique miRNA profiles of fractionated milk.

Human milk (HM) contains regulatory biomolecules including miRNAs, the origin and functional significance of which are still undetermined. We used TaqMan OpenArrays to profile 681 mature miRNAs in HM cells and fat, and compared them with maternal peripheral blood mononuclear cells (PBMCs) and plasma, and bovine and soy infant formulae. HM cells and PBMCs (292 and 345 miRNAs, respectively) had higher miRNA content than HM fat and plasma (242 and 219 miRNAs, respectively) (p < 0.05). A strong association in miRNA profiles was found between HM cells and fat, whilst PBMCs and plasma were distinctly different to HM, displaying marked inter-individual variation. Considering the dominance of epithelial cells in mature milk of healthy women, these results suggest that HM miRNAs primarily originate from the mammary epithelium, whilst the maternal circulation may have a smaller contribution. Our findings demonstrate that unlike infant formulae, which contained very few human miRNA, HM is a rich source of lactation-specific miRNA, which could be used as biomarkers of the performance and health status of the lactating mammary gland. Given the recently identified stability, uptake and functionality of food- and milk-derived miRNA in vivo, HM miRNA are likely to contribute to infant protection and development.

Gene expression in breastmilk cells is associated with maternal and infant characteristics.

Breastmilk is a rich source of cells with a heterogeneous composition comprising early-stage stem cells, progenitors and more differentiated cells. The gene expression profiles of these cells and their associations with characteristics of the breastfeeding mother and infant are poorly understood. This study investigated factors associated with the cellular dynamics of breastmilk and explored variations amongst women. Genes representing different breastmilk cell populations including mammary epithelial and myoepithelial cells, progenitors, and multi-lineage stem cells showed great variation in expression. Stem cell markers ESRRB and CK5, myoepithelial marker CK14, and lactocyte marker α-lactalbumin were amongst the genes most highly expressed across all samples tested. Genes exerting similar functions, such as either stem cell regulation or milk production, were found to be closely associated. Infant gestational age at delivery and changes in maternal bra cup size between pre-pregnancy and postpartum lactation were associated with expression of genes controlling stemness as well as milk synthesis. Additional correlations were found between genes and dyad characteristics, which may explain abnormalities related to low breastmilk supply or preterm birth. Our findings highlight the heterogeneity of breastmilk cell content and its changes associated with characteristics of the breastfeeding dyad that may reflect changing infant needs.

Milk ejection patterns: an intra- individual comparison of breastfeeding and pumping.

BACKGROUND: Milk ejection is a transient episode critical to milk removal and women typically have multiple milk ejections during breastfeeding and pumping. Recently it was found that milk ejection characteristics such as number of milk ejections and periodicity were consistent throughout 12 months of lactation in women who expressed their milk with an electric breast pump. It is not known whether the stimulation of an infant at the breast influences milk ejection patterns or whether this is a programmed event. The aim of this study was to compare milk ejection patterns during breastfeeding and expressing milk with an electric pump within mothers. METHODS: Twelve lactating mothers with normal milk production (502-1356 mL) had milk ejection recorded by measuring the diameter of a major milk duct with ultrasound imaging throughout an entire breastfeed and a 15-min pumping session. Scans were analysed for timing, duration of duct dilation and maximum duct diameter. RESULTS: The initial milk ejection defined as the first increase in duct diameter was observed earlier during breastfeeding than during two phase pumping sessions but was not statistically significant (p = .057). There were no significant differences between the duration of the first or second milk ejection for mothers when breastfeeding or pumping at their maximum comfortable vacuum (p = .18; p = .99). The times taken to reach the peak duct diameter, or the first half of the milk ejection were also not found to be significantly different between breastfeeding and pumping. CONCLUSION: This study suggests that milk ejection patterns remain consistent within individual mothers regardless of whether the mother is breastfeeding or expressing milk indicating a likelihood of the process either being programmed or innate to the individual.

Asynchronous milk ejection in human lactating breast: case series.

BACKGROUND: Milk production is under the influence of autocrine control such that the rate of milk synthesis decreases as the breast fills with milk. Effective elimination of milk from the alveoli via the milk ejection reflex will therefore result in increased milk synthesis. It has been assumed that milk ejection occurs in all alveoli simultaneously; however, animal studies have indicated that full alveoli eject milk sooner than less full alveoli, suggesting heterogeneous emptying of the mammary gland. OBJECTIVE: The aim of this study was to determine whether milk ejection occurs asynchronously in the human lactating breast. METHODS: Retrospective analysis of videos made of ultrasound monitoring of milk ducts during pumping. Six video clips (4 women) of ultrasound monitored milk ejections showed obvious differences in the timing of milk flow between different main milk ducts. Duct diameter was simultaneously measured every second in 2 different ducts that drained 2 separate lobes of the breast. RESULTS: For 5 of 6 ultrasound duct monitoring sessions, both duct dilation and visualization of milk flow in the 2 separate main milk ducts differed by 2 to 8 seconds. For the remaining woman, milk was observed to eject from 1 part of the lobe, and when not removed, it flowed in a retrograde fashion into a different part of the lobe. CONCLUSION: Asynchrony of milk ejection occurs in the human lactating breast, suggesting that the timing of myoepithelial cell response differs, resulting in heterogeneous emptying of the gland.

Smoking prevalence, readiness to quit and smoking cessation in HIV+ patients in Germany and Austria.

INTRODUCTION: Due to the interaction between smoking and the virus and the antiretroviral therapy, the excess health hazard due to smoking is higher in HIV+ patients than in the general population. International studies suggest a higher prevalence of smoking in HIV+ subjects compared to the general population. It was the aim of the study to assess prevalence of smoking, to analyze determinants of smoking, and to evaluate readiness to quit in HIV+ patients in Germany and Austria. MATERIAL AND METHODS: Consecutive patients with positive tested HIV status, smokers and non-smokers, who are treated in seven different HIV care centres in Austria and Germany were included. Nicotine dependence was assessed with the Fagerström Test for Nicotine Dependency (FTND), and stages of change by a standardized readiness to quit questionnaire. Self-reported smoking status was objectified by measuring exhaled carbon monoxide levels. Smokers who wanted to quit were offered a structured smoking cessation programme, and those who did not want to quit received a 1-minute consultation. After six months, the smoking status of all included subjects was reassessed. RESULTS: A total of 447 patients were included; the response rate was 92%. Prevalence of smoking was 49.4%. According to a multivariate logistic regression analysis, lower age, male sex, lower educational level, and smoking of the partner were significantly associated with the smoking status. According to the FTND, 25.3% showed a low (0-2 points), 27.6 a moderate (3-4 points) and 47.1% a high (5-10 points) dependency. Regarding stages of change, 15.4% of the smokers were in the stadium precontemplation, 48.4 in contemplation, 15.4 in preparation and 10.0 in the stadium action. 11.0% were not assignable in any stadium. Higher education level and lower grade of dependency were significantly associated with the wish to quit smoking. Six months after the baseline examination, smoking cessation visits (at least one session) was performed in 28.5% of the smokers. 13% of the smokers have quit smoking, 23% have reduced smoking and 63% did not change smoking habits positively 6 months after the first visit. CONCLUSIONS: Prevalence rates for smoking in HIV+ subjects are higher than in the general population. Readiness to quit is, however, high, and 13% of smokers who have quit smoking after six months is a remarkable short-term success. This observation underlines the importance and feasibility of addressing smoking habits in HIV care.

Expression of the Pluripotency Transcription Factor OCT4 in the Normal and Aberrant Mammary Gland.

Breast cancers with lactating features, some of which are associated with pregnancy and lactation, are often poorly differentiated, lack estrogen receptor, progesterone receptor, and HER2 expression and have high mortality. Very little is known about the molecular mechanisms that drive uncontrolled cell proliferation in these tumors and confer lactating features. We have recently reported expression of OCT4 and associated embryonic stem cell self-renewal genes in the normal lactating breast and breastmilk stem cells (hBSCs). This prompted us to examine OCT4 expression in breast cancers with lactating features and compare it with that observed during normal lactation, using rare specimens of human lactating breast. In accordance with previous literature, the normal resting breast (from non-pregnant, non-lactating women) showed minimal OCT4 nuclear expression (0.9%). However, this increased in the normal lactating breast (11.4%), with further increase in lactating adenomas, lactating carcinomas, and pregnancy-associated breast cancer (30.7-48.3%). OCT4 was expressed in the epithelium and at lower levels in the stroma, and was co-localized with NANOG. Comparison of normal non-tumorigenic hBSCs with OCT4-overexpressing tumorigenic breast cell lines (OTBCs) demonstrated upregulation of OCT4, SOX2, and NANOG in both systems, but OTBCs expressed OCT4 at significantly higher levels than SOX2 and NANOG. Similar to hBSCs, OTBCs displayed multi-lineage differentiation potential, including the ability to differentiate into functional lactocytes synthesizing milk proteins both in vitro and in vivo. Based on these findings, we propose a hypothesis of normal and malignant transformation in the breast, which centers on OCT4 and its associated gene network. Although minimal expression of these embryonic genes can be seen in the breast in its resting state throughout life, a controlled program of upregulation of this gene network may be a potential regulator of the normal remodeling of the breast toward a milk-secretory organ during pregnancy and lactation. Deregulation of this gene network either within or outside pregnancy and lactation may lead to aberrant breast cell proliferation and malignant transformation, suggesting a role of these genes in both normal lactation and breast oncogenesis.

Cells in human milk: state of the science.

Reflecting millions of years of adaptation and optimization, milk is unique to the species that produces it and for the young of which it is intended, with large variations in both lactation strategies and milk composition existing among different mammalian species. Despite this, milk has the consistent function of providing nourishment, protection, and developmental programming to the young, with short- and long-term effects. Among its components that confer these functions, breast milk contains maternal cells, from leukocytes to epithelial cells of various developmental stages that include stem cells, progenitor cells, lactocytes, and myoepithelial cells. Although in the first 150 years since their discovery, breast milk cells were mostly studied for their morphological traits, technological advances in the last decade have allowed characterization of breast milk cell types at the protein and messenger RNA levels. This is now paving the way for investigation of the functions of these cells in the breastfed infant and the use of breast milk as a tool to understand the normal biology of the breast and its pathologies. This review summarizes the current knowledge of breast milk cellular heterogeneity and discusses future prospects and potential applications.

Spectrophotometric measurements of human tissues for the detection of subjacent blood vessels in an endonasal endoscopic surgical approach.

Thin slices of human tissues are characterized concerning reflection and transmission in a wavelength range from 400 to 1700 nm. The results are primarily useful to find a wavelength for the detection of subjacent blood vessels during surgical procedures, especially neurological surgery. The measurements have been conducted using a customized measuring station, utilizing two halogen bulb lamps and two spectrometers. This paper focuses on creating a data base with the optical properties of artery, brain, bone, nasal mucosa, and nerve. The spectral distributions are compared among each other, similarities and differences are pointed out. Each tissue has got unique spectral characteristics, whereas typical absorption bands can be found in the overall tissues, especially hemoglobin and water absorption bands. The reflectivity maxima are typically located in the red or near-infrared. All the transmission maxima are located between 1075 nm and 1100 nm. The measurements have been conducted at the Institute of Anatomy at the University of Leipzig.

[Multivariate prediction of breeding values for canine hip and elbow dysplasia as well as humeral osteochondrosis in the Bernese mountain dog]. / Multivariate Zuchtwertschätzung für Hüft- und Ellbogengelenkdysplasie sowie Osteochondrose des Schultergelenks beim Berner Sennenhund.

The aim of this study was the multivariate prediction of breeding values for canine hip dysplasia (CHD), elbow dysplasia (ED) and humeral osteochondrosis (OCD) for Bernese mountain dogs of the Schweizer Sennenhund-Verein für Deutschland e. V. (SSV). For the analysis the pedigrees of eight generations and radiographic screening results of the birth cohorts from 1995-2008 were used. The number of dogs with scores for CHD was 5513, for ED 5175 and OCD 1240. Breeding values were multivariately predicted using a mixed linear model for CHD, ED and OCD as well as for the occurrence of a fragmented coronoid process of the medial ulna (FCP) and the ED-score without FCP. The pedigree breeding value (eRZWp) which is used as the selection criterion reached a reliability to predict the phenotype of the offspring at 2.8-2.9% for CHD, 2.9% for ED, 1.1% for ED without FCP, 1.8% for FCP and 0.8-1.3% for OCD. The reason for the low predictive value of the eRZW(P) is caused by the very high influence of the own performance of the animal and the very uniform distribution of contributions of the breeding values of the relatives.These results indicate that even a multivariate prediction of breeding values does not lead to a faster progress in breeding against CHD and ED, however, does allow breeding against OCD in the Bernese mountain dog. In comparison to phenotypic selection, there is some improvement in the selection response when using breeding values. Due to the general low predictive power of breeding values better approaches for selection of future breeding animals are urgently warranted to achieve improvements in breeding Bernese mountain dogs.

The association of Raynaud's syndrome with cisplatin-based chemotherapy - a meta-analysis.

BACKGROUND: Vasospastic disorders of the digital circulation such as the Raynaud's syndrome (RS) are known side-effects of treatment of cisplatin-based chemotherapy. The prevalence of RS in patients during treatment with cisplatin-based chemotherapy is not well-defined. OBJECTIVE: The objective of this paper was to assess the prevalence of RS in patients receiving cisplatin-based chemotherapy - a meta-analysis of published data was performed. MATERIAL AND METHODS: The PubMed database of the National Library of Medicine and ISI Web of Knowledge was used for studies dealing with RS and patients receiving cisplatin-based chemotherapy. The studies provided sufficient data to estimate the prevalence of RS in patients receiving cisplatin-based chemotherapy. A forest plot was determined by the revealed prevalences. Statistical analysis was based on methods for a random effects meta-analysis and a finite mixture model for proportions. Publication bias was investigated with the linear regression test (Egger's method). A meta-regression was conducted by the year of publication and latitude. RESULTS: 24 eligible studies, contributing data on 2749 subjects, were included in this meta-analysis. For RS in patients receiving cisplatin-based chemotherapy a pooled prevalence of 24% and 95% CI (0.175, 0.313) was obtained. A mixture model analysis found four latent classes. Statistically, publication bias was not present (p-value 0.74). The meta-regression indicated that the odds ratio increased when the latitude increased, too (p-value 0.011). CONCLUSION: Despite some heterogeneity there is a possible indication of an association between RS and patients receiving cisplatin-based chemotherapy.

Breastmilk is a novel source of stem cells with multilineage differentiation potential.

The mammary gland undergoes significant remodeling during pregnancy and lactation, which is fuelled by controlled mammary stem cell (MaSC) proliferation. The scarcity of human lactating breast tissue specimens and the low numbers and quiescent state of MaSCs in the resting breast have hindered understanding of both normal MaSC dynamics and the molecular determinants that drive their aberrant self-renewal in breast cancer. Here, we demonstrate that human breastmilk contains stem cells (hBSCs) with multilineage properties. Breastmilk cells from different donors displayed variable expression of pluripotency genes normally found in human embryonic stem cells (hESCs). These genes included the transcription factors (TFs) OCT4, SOX2, NANOG, known to constitute the core self-renewal circuitry of hESCs. When cultured in the presence of mouse embryonic feeder fibroblasts, a population of hBSCs exhibited an encapsulated ESC-like colony morphology and phenotype and could be passaged in secondary and tertiary clonogenic cultures. While self-renewal TFs were found silenced in the normal resting epithelium, they were dramatically upregulated in breastmilk cells cultured in 3D spheroid conditions. Furthermore, hBSCs differentiated in vitro into cell lineages from all three germ layers. These findings provide evidence that breastmilk represents a novel and noninvasive source of patient-specific stem cells with multilineage potential and establish a method for expansion of these cells in culture. They also highlight the potential of these cells to be used as novel models to understand adult stem cell plasticity and breast cancer, with potential use in bioengineering and tissue regeneration.

Receptor activator of NF-κB ligand promotes proliferation of a putative mammary stem cell unique to the lactating epithelium.

In mice, CD49f(hi) mammary stem cells (MaSCs) asymmetrically divide to generate CD49f(+) committed progenitor cells that differentiate into CD49f(-) phenotypes of the milk-secreting tissue at the onset of pregnancy. We show CD49f(+) primary mammary epithelial cells (PMECs) isolated from lactating tissue uniquely respond to pregnancy-associated hormones (PAH) compared with CD49f(+) cells from nonlactating tissue. Differentiation of CD49f(+) PMEC in extracellular matrix produces CD49f(-) luminal cells to form differentiated alveoli. The PAH prolactin and placental lactogen specifically stimulate division of CD49f(-) luminal cells, while receptor activator of nuclear factor (NF)-κB ligand (RANKL) specifically stimulates division of basal CD49f(+) cells. In nondifferentiating conditions, we observed a greater proportion of multipotent self-renewing cells, and RANKL treatment activated the RANK pathway in these cultures. Furthermore, we observed the deposition of calcium nodules in a proportion of these cells. These data imply that a MaSC unique to the lactating breast exists in humans, which generates progeny with discrete lineages and distinct response to PAH.

Blood flow characteristics of the human lactating breast.

BACKGROUND: Despite the increased metabolic activity of the lactating breast, no studies have been carried out to determine mammary blood flow (MBF) parameters or the relationship between MBF and milk production in women. The aim of this study was to measure the MBF in the internal mammary artery (IMA) and lateral thoracic artery (LTA) of lactating women and determine if these were related to milk production. METHODS: Blood flow in the IMA and LTA was measured with color Doppler ultrasound in 55 lactating women. Twenty-four-hour milk production was determined with the test-weigh method. RESULTS: IMA contributed the greater proportion of blood flow to the lactating breast (70%). MBF was highly variable between women but consistent between the left (126 L/24 h; interquartile range, 76-169) and right (110 L/24 h) breasts. No relationship between MBF and milk production was demonstrated. For 3 women, MBF was markedly reduced in 1 breast that was synthesizing almost no milk compared to the other that was producing a normal volume of milk. DISCUSSION: Although no relationship between MBF and milk production was found, the substantial reduction in blood flow in the breasts of lactating women producing almost no milk suggests a threshold below which milk production is compromised. CONCLUSION: Doppler ultrasound did not demonstrate a relationship between MBF and milk production in lactating women. Further investigation is required to fully understand the role of blood flow in milk synthesis.

Tongue movement and intra-oral vacuum of term infants during breastfeeding and feeding from an experimental teat that released milk under vacuum only.

BACKGROUND: Recent literature supports the theory that vacuum is integral to the removal of milk from the breast rather than peristaltic compression of the breast. AIM: We aimed to determine if breastfed infants could remove breast milk from an experimental teat designed to release milk only when a vacuum is applied. METHODS: Submental ultrasound images and intra-oral vacuum measurements were recorded simultaneously during both a breastfeed and a feed with the experimental teat. RESULTS: Infants placed the nipple and teat a similar distance from the nipple hard-soft palate junction when the tongue was lowered (4.7 mm vs 5.3 mm). As the tongue lowered the nipple and teat expanded evenly although the nipple expanded more than the teat (3.1mm vs 1.5 mm). Both baseline (-31 mm Hg vs -12 mm Hg) and peak vacuum (-122 mm Hg vs -67 mm Hg) applied to the breast were significantly higher than for the teat. CONCLUSION: Breastfed infants are able to remove milk from a teat using only vacuum with a similar tongue movement to that of breastfeeding. This evidence supports the theory that vacuum is a critical factor in the removal of milk from the breast.

14-3-3σ (sigma) regulates proliferation and differentiation of multipotent p63-positive cells isolated from human breastmilk.

The mammary gland is a dynamic organ that only undergoes complete differentiation during pregnancy. Differentiation is fuelled by asymmetric division of stem cells that reside in normally quiescent niches in the resting gland in response to pregnancy-associated hormones. Loss of regulation of stem cells is believed to underlie some breast cancers. This process is poorly understood in humans since it is difficult to extract stem cells from the lactating gland. We have identified a p63-positive population in breastmilk that proliferates and differentiates into at least two separate mammary lineages in culture. Nuclear translocation of p63 coincides with expression of the cell-cycle arrest protein 14-3-3σ (Sigma) and precedes differentiation. Transient down-regulation of Sigma promotes maintenance of the p63-positive population without affecting normal differentiation. We propose that p63-postive cells from breastmilk represent a novel source of cells to model regulation of mammary gland development and tumorigenesis.

[Multivariate genetic analysis of canine hip and elbow dysplasia as well as humeral osteochondrosis in the Bernese mountain dog]. / Multivariate genetische Analyse der Hüft- und Ellbogengelenkdysplasie sowie der Osteochondrose des Schultergelenks beim Berner Sennenhund.

In the present study genetic parameters for canine hip dysplasia (CHD), canine elbow dysplasia (CED) and osteochondrosis dissecans of the humeral head (OCD) were analysed in Bernese mountain dogs. The data set included the official scores for CHD and CED from 5534 Bernese mountain dogs born in the years 1995-2008. A multivariate linear animal model was employed to estimate heritabilities, additive genetic and residual correlations using residual maximum likelihood (REML). Heritability estimates were h2 = 0.26 for CHD, h2 = 0.22 for CED and h2 = 0.40 for OCD. The additive genetic correlation between CHD and CED was 0.31, between CHD and OCD 0.25, and between CED und OCD -0.49. A further multivariate analysis of the prevalence of the FCP (fragmented coronoid processus), CHD and OCD revealed a heritability of h2 = 0.59 for FCP. The additive genetic correlations among FCP and CHD as well CED except FCP were positive, but negative with OCD. Multivariately estimated breeding values will lead to higher genetic progress because the correlation structure of the traits can be taken into account and possible genetic antagonisms among traits are better reflected in the breeding values.

Disrupted secretory activation of the mammary gland after antenatal glucocorticoid treatment in sheep.

Antenatal glucocorticoids are administered to women at risk of preterm delivery to prevent neonatal respiratory morbidity. The effects of exogenous glucocorticoids on the development of lactation are unknown. This study investigated the effects of a single dose of antenatal glucocorticoids on secretory activation in sheep before and after parturition. Pregnant ewes (N=36) were randomised to receive either medroxyprogesterone acetate (MPA) at 118 days of pregnancy and betamethasone at 125 days (BETA group), MPA at 118 days and saline at 125 days (MPA group) or saline at 118 and 125 days (SALINE group). The concentration of lactose, progesterone, cortisol and prolactin in maternal plasma was measured during pregnancy. After term parturition, the concentration of lactose in milk and maternal plasma was measured daily for 5 days. Lambs were weighed at birth and at 5 days of age; milk volume was measured on day 5. The concentration of lactose in maternal plasma increased significantly after betamethasone administration, corresponding to a fall in plasma progesterone. No changes in lactose were observed in MPA or SALINE ewes. Transient decreases in cortisol and increases in prolactin were observed in the BETA group, but not in either the MPA or SALINE group. After parturition, BETA ewes experienced reduced milk yield and lamb weight gain, and delayed increases in milk lactose levels compared with MPA and saline controls. This study demonstrated that, in sheep, antenatal glucocorticoid administration disrupted secretory activation, causing precocious mammary secretion before parturition and compromising postpartum milk production and lamb growth.

Initiation of human lactation: secretory differentiation and secretory activation.

Theories for the origin of milk have been recorded since the time of Ancient Greeks. In those times it was believed that milk was derived from special vessels that connected the uterus to the breasts. The "chyle theory" on the origin of milk was another prominent theory which persisted well into the nineteenth century before the realisation that milk components were derived from blood and some milk constituents were actually synthesized within the breasts. The demonstration that milk ejection was the expulsion of milk that had already been secreted and that milk secretion was a separate continuous process, set the background for the development for the current understanding of milk synthesis and secretion. Today we know that there are two stages in the initiation of lactation- secretory differentiation and secretory activation. Secretory differentiation represents the stage of pregnancy when the mammary epithelial cells differentiate into lactocytes with the capacity to synthesize unique milk constituents such as lactose. This process requires the presence of a 'lactogenic hormone complex' of the reproductive hormones, estrogen, progesterone, prolactin and some metabolic hormones. Secretory activation on the other hand, is the initiation of copious milk secretion and is associated with major changes in the concentrations of many milk constituents. The withdrawal of progesterone triggers the onset of secretory activation but prolactin, insulin and cortisol must also be present. This review describes the works of pioneers that have led to our current understanding of the biochemical and endocrinological processes involved in the initiation of human lactation.