Historical Perspectives of Prolactin and Growth Hormone as Mammogens,Lactogens and Galactagogues—Agog for the Future!

Around 80 years ago researchers first established that the pituitary gland regulates mammary gland function as demonstrated by the ability of its extracts to promote both mammogenesis and lactogenesis in animal models. Little did they realize that in fact two hormones, prolactin (PRL) and growth hormone (GH), were contributing to these effects. By the mid 1930s PRL had been purified as a distinct lactogen, while the galactopoietic effect of GH was confirmed after its purification in the 1940s. Interest in these hormones initially centered about their potential for increasing milk production, while in the latter half of the twentieth century it became obvious that these hormones also had the potential to influence mammary cancer development. During the past 50 years large strides have been made into understanding how these hormones signal to, and within, cells of the mammary gland, paralleling rapid developments in the fields of cellular and molecular biology. In compiling this review we have summarized the progress that has been made to date regarding roles for these hormones in the mammary gland, with a goal of ensuring that some of the seminal literature is not diluted or forgotten. In doing so it is clear that there are lessons to be learned from past experiences, where new methods and technologies will continue to present exciting new opportunities to revisit lingering questions regarding these fascinating hormones and this fascinating organ.     

Control of Milk Secretion and Apoptosis DuringMammary Involution

Lactation depends on regular suckling or milkingof the mammary gland. Without this stimulus, milksecretion stops and mammary involution is induced.Involution caused by abrupt cessation of milk removal is characterized by de-differentiation andapoptosis of mammary epithelial cells, the extent andtime course of the latter varying between species.Apoptosis is inhibited and milk secretion is restored by re-suckling, if milk stasis is of shortduration. Mammary involution and apoptosis also occurduring weaning, even in concurrently-pregnant animalswhen the interval between lactations is restricted, suggesting that tissue remodeling is essentialfor subsequent lactation. Declining milk production inruminants after peak lactation is also associated with,and probably results from, net cell loss by apoptosis. Involution and apoptosis arecontrolled by changes in systemic galactopoietic hormonelevels, and by intra-mammary mechanisms responsive tomilk removal. Milk stasis precipitated by litter removal or cessation of milking may involveintra-mammary control related to physical distension ofthe epithelium. Local control of apoptosis in rodentsduring weaning, and after peak lactation in dairyanimals, may be due to the actions of milk-bornesurvival factors or their inhibitors, and can bemanipulated by frequency of milk removal.     

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.     

Feedback control of milk secretion from milk

Extracellular storage allows biologically-active substances in milk to influence mammary function. Among these factors is one which regulates the rate of milk secretion acutely according to frequency or completeness of milk removal in each mammary gland. The active factor in goat's milk has been identified by screening milk constituents for their ability to inhibit milk constituent secretion in tissue and cell culture bioassays, and found to be a novel milk protein. The proteins identified by bioassayin vitro, also inhibited milk secretion in lactating goats in a reversible, concentration-dependent manner. This protein, termed FIL (feedback inhibitor of lactation), acts by reversible blockade of constitutive secretion in the mammary epithelial cell. As the inhibitor is synthesized in the same epithelial cells, feedback inhibition is, therefore, an autocrine mechanism. FIL's unusual mechanism of action also influences other aspects of mammary function. Acute disruption of mammary membrane trafficking is associated with downregulation of prolactin receptors and followed by a decrease in epithelial cell differentiation. Thus, in addition to acutely-regulating milk secretion, FIL may induce the adaptation in mammary cell differentiation which actsin vivo to sustain the secretory response to a sustained change in milk removal. In the long term, matching of milk output to demand is achieved by a change in mammary cell number. This developmental response is also local in nature. Whether it too is due to autocrine modulation by FIL of mechanisms influencing cell proliferation or survival, or elicited by another milk-borne factor, remains to be determined.     

Cholesterol Transport and Regulation in the Mammary Gland

The milk-producing alveolar epithelial cells secrete milk that remains after birth the principal source of nutrients for neonates. Milk secretion and composition are highly regulated processes via integrated actions of hormones and local factors which involve specific receptors and downstream signal transduction pathways. Overall milk composition is similar among mammalian species, although the content of individual constituents such as lipids may significantly differ from one species to another. The milk lipid fraction is essentially composed of triglycerides, which represent more than 95 % of the total lipids in human and commercialized bovine milk. Though sterols, including cholesterol, which is the major milk sterol, represent less than 0.5 % of the total milk lipid fraction, they are of key importance for several biological processes. Cholesterol is required for the formation of biological membranes especially in rapidly growing organisms, and for the synthesis of sterol-based compounds. Cholesterol found in milk originates predominantly from blood uptake and, to a certain extent, from local synthesis in the mammary tissue. The present review summarizes current knowledge on cellular mechanisms and regulatory processes determining intra- and transcellular cholesterol transport in the mammary gland. Cholesterol exchanges between the blood, the mammary alveolar cells and the milk, and the likely role of active cholesterol transporters in these processes are discussed. In this context, the hormonal regulation and signal transduction pathways promoting active cholesterol transport as well as potential regulatory crosstalks are highlighted.     

Regulation of renal tubular secretion of organic compounds

BACKGROUND: Information on the molecular basis underlying organic anion and cation transport in renal tubules has expanded in recent years with the identification and characterization of numerous transporters. However, little is known about the regulation of this transport. METHODS: Both English and Russian language studies dealing with the regulation of organic ion transport by the kidney have been reviewed. RESULTS: This review summarizes the literature on the physiological and pharmacological aspects of the regulation of organic ion transport, linking this information where possible to underlying transport mechanisms. Current models of the tubular secretion of organic anions and cations are reviewed. Factors that inhibit or enhance tubular secretion of xenobiotics are described, and their influence on proximal tubule cell transport and function is discussed. Important roles for substrate stimulation, the adrenergic nervous system, numerous hormones, P-glycoprotein, and protein kinase C activity have been identified. CONCLUSIONS: Despite considerable advances in the understanding of basic transport pathways and mechanisms involved in the tubular secretion of organic compounds, there is still relatively little information on the regulation of this transport. Studies combining the techniques of integrative and cell physiology and molecular biology will provide significant new insights into the pathways regulating the tubular transport of these compounds.     

RAS与胰腺炎发病及治疗的研究新进展

传统上认为，肾素-血管紧张素系统（renin angiotensin aldosterone system，RAS）在血压、体液、电解质平衡的调节中起到重要作用。越来越多研究发现，除了循环系统中的RAS，局部RAS存在于各种组织。胰腺内源性RAS调节胰岛激素和导管离子分泌，并借此来调控胰腺内、外分泌功能，它在缺氧时上调、参与组织炎症发生、通过自由基直接或间接引起胰腺损害。现已有人研究RAS与胰腺炎病理生理机制的关系，并提出RAS治疗急性胰腺炎的新思路。     

Paraneoplastic syndromes associated with urogenital tumours: an up-to-date review

Paraneoplastic syndromes induced by inappropriate-ectopic production of hormones, cytokines and growth factors, therefore not mediated directly by local infiltration or metastatic spread, occur in approximately 10 per cent of patients with malignant disease in initial phase. Subjects with paraneoplastic syndromes often are affected by small occult tumors which may be diagnosed only at autopsy. Inappropriate secretion of peptide hormones is the commonest cause of paraneoplastic syndromes. On the basis of an up-to-date review of the literature, this article discusses pathogenetic mechanisms, diagnostic features and essential therapeutic measures concerning the syndromes of inappropriate ACTH/CRH, PTHrp, TRH/TSH, ADH and MSH secretion. Moreover, some of paraneoplastic syndromes, that are associated with production of cytokines and growth factors by either tumor- or non malignant host microenvironment -cells, are briefly outlined.     

TGFβ as a Potential Mediator of Progesterone Action in the Mammary Gland of Pregnancy

The molecular mechanisms controlling the onset of copious milk secretion are only now beginning to be elucidated. We have known for nearly four decades that progesterone suppresses milk secretion during pregnancy, and that the fall in progesterone near parturition is necessary for secretory activation. Similarly, we’ve known for 15 years that transforming growth factor β (TGFβ) also suppresses milk secretion. Yet no formal link between the two has ever been established. This work aims to review the evidence for and against a link between progesterone and TGFβ, raise unanswered questions, and to propose further lines of research. This work was supported by NIH PO1-HD38129, Margaret C. Neville, PI.     

Milk lipid globules and their surrounding membrane: a brief history and perspectives for future research

Most of the lipids in milk are triacylglycerols that occur in globules surrounded by a membrane derived from cellular membranes. This membrane, the milk-fat or milk-lipid globule membrane (MLGM),² surrounds globules during the process of their secretion from the cell. The nature and cellular origin of the milk lipid globule membrane has been the subject of a considerable amount of research. Milk lipid globules originate as very small lipid droplets formed on or in the endoplasmic reticulum followed by release into the cytosol. These droplets consist of a triacylglycerol-rich core coated with a layer of proteins and polar lipids. How these droplets are formed, how they can grow in volume, how they move through the cell, and how they are secreted are questions that have been the basis for a number of investigations. While the general outlines of droplet formation, growth, movement, and secretion are known, virtually no molecular details of any of these processes have been elucidated. In this article I have presented a brief historical account of research on milk fat globules, their surrounding membrane, and on aspects of the intracellular origin, growth, and secretion of milk lipid globules. I have also attempted to call attention to those areas where further research is needed to gain a better understanding of the processes involved.     

Secretion and Fluid Transport Mechanisms in the Mammary Gland: Comparisons with the Exocrine Pancreas and the Salivary Gland

Milk is a complex fluid composed of proteins, sugars, lipids and minerals, in addition to a wide variety of bioactive molecules including vitamins, trace elements and growth factors. The composition of these components reflects the integrated activities of distinct synthetic, secretion and transport processes found in mammary epithelial cells, and mirrors the differing nutritional and developmental requirements of mammalian neonates. Five general pathways have been described for secretion of milk components. With the exception of lipids, which are secreted a unique pathway, milk components are thought to be secreted by adaptations of pathways found in other secretory organs. However little is known about the molecular and cellular mechanisms that constitute these pathways or the physiological mechanisms by which they are regulated. Comparisons of current secretion and transport models in the mammary gland, exocrine pancreas and salivary gland indicate that significant differences exist between the mammary gland and other exocrine organs in how proteins and lipids are packaged and secreted, and how fluid is transported.     

Gut Hormones and Leptin: Impact on Energy Control and Changes After Bariatric Surgery—What the Future Holds

Obesity is now considered the new world epidemic. In an attempt to face this menace to public health, several treatments, apart from the traditional nutritional modification and oral medication, have been introduced, among them bariatric surgery and gut hormone-based treatments. The gastrointestinal (GI) tract is a powerful endocrine organ, releasing active peptides and influencing appetite and glycaemic control. Alteration of the GI tract, in ways that exaggerate the secretion and levels of the gut hormones, creates a new functional equilibrium that further contributes to weight loss. The purpose of this review is to explore the mechanisms that drive this gut hormone-derived body regulation, as well as the changes that occur to them after bariatric surgery. Close to that, leptin, a hormone secreted by adipose tissue will be analysed, as its pathways are closely related to those of the gut hormones. Gut hormones are strongly implicated in energy control, and various effects of bariatric surgery in weight loss are directly related to the alteration of the levels of these hormones.     

Cyclic AMP.

Cyclic AMP is believed to be the intracellular agent which mediates the action of many hormones on their target cell. The mechanisms by which the nucleotide controls glycogen metabolism in liver and skeletal muscle seem to be firmly established. Data relevant to this area of research are selectively reviewed. In addition, the evidence is reviewed for and against a role for cyclic AMP in the regulation of a variety of other cellular functions including: cardiac contractility, smooth muscle relaxation, platelet aggregation, salivary gland amylase secretion, pancreatic exocrine secretion, and gastric acid secretion.     

Hormonal regulation of mammary differentiation and milk secretion

The endocrine system coordinates development of the mammary gland with reproductive development and the demand of the offspring for milk. Three categories of hormones are involved. The levels of the reproductive hormones, estrogen, progesterone, placental lactogen, prolactin, and oxytocin, change during reproductive development or function and act directly on the mammary gland to bring about developmental changes or coordinate milk delivery to the offspring. Metabolic hormones, whose main role is to regulate metabolic responses to nutrient intake or stress, often have direct effects on the mammary gland as well. The important hormones in this regard are growth hormone, corticosteroids, thyroid hormone, and insulin. A third category of hormones has recently been recognized, mammary hormones. It currently includes growth hormone, prolactin, PTHrP, and leptin. Because a full-term pregnancy in early life is associated with a reduction in breast carcinogenesis, an understanding of the mechanisms by which these hormones bring about secretory differentiation may offer clues to the prevention of breast cancer.     

Mechanisms of ovulation in mammalian females]

The aim of this review was to briefly recapitulate the most important mechanisms involved in ovulation in the Mammals. The rabbit served as a model for the study of reflex ovulation. The triggering of ovulation by coitus was shown to be dependent on the activation of the hypothalamo-pituitary axis by sensory signals of multiple origin. The fundamental aspects of the hormonal and nervous machinery that governs spontaneous ovulation have been envisaged. The timing of LH ovulatory release and the mechanisms of action of this hormone at the ovarian level have been defined. Evidence was given that steroid hormones from ovarian and/or adrenal origin could evoke or modulate ovulatory processes. The structures responsible for both the tonic and clonic secretion of LH in subprimate and in primate mammals have been localized in the hypothalamus. The nervous endocrine mechanisms involving interactions between LHRH, neurotransmitters, prostaglandins and steroid hormones have been elucidated. Short loop feed back effects of pituitary hormones were shown to control LHRH secretion. Several examples were given attesting that the limbic system, the thalamus and the neocortex on one hand, and the environmental factors, on the other hand, were capable of modulating the activity of the hypothalamic structures implicated in the control of either ovulation or estrous rhythm regulation. An unitarian conception of the ovulatory mechanisms, based on the fact that coital-induced ovulation and estrogen-induced ovulation could occur in spontaneous and reflex ovulators respectively, has been proposed.     

Hypothalamic and pituitary function

The endocrine system consists of groups of cells (glands) that secrete messengers (hormones), which affect distant groups of cells (target organs). It controls mainly basal processes. Hormonal action may be on receptors in the target cell membrane (e.g. leading to alterations in membrane channel properties), in which case it is rapid, or it may affect gene function and thus protein synthesis, in which case the onset of action is relatively slow. Endocrine function is controlled via single and multiple feedback mechanisms from products of the various target organs. It is largely under the control of the hypothalamus via the pituitary gland. Releasing factors and hormones from the hypothalamus act on the pituitary, which produces its own hormones (antidiuretic hormone, oxytocin, growth hormone and prolactin) as well as hormones and releasing factors that affect other endocrine glands (adrenocorticotrophic hormone, thyroid stimulating hormone, luteinizing hormone and follicle stimulating hormone). Growth hormone controls skeletal growth via the release of insulin-like growth factors from the liver; it promotes anabolism, but also antagonizes the hypoglycaemic effect of insulin. Antidiuretic hormone secretion is stimulated by changes in osmolality and is a sensitive mechanism for conserving fluid via its action on the kidney. Oxytocin stimulates uterine contraction, and prolactin stimulates milk production. Luteinizing and follicle stimulating hormones affect the growth of the gonads.     

Alveolar and Lactogenic Differentiation

The mouse mammary gland is a complex tissue that proliferates and differentiates under the control of systemic hormones during puberty, pregnancy and lactation. Once a highly branched milk duct system has been established, during mid/late pregnancy, alveoli, little saccular outpouchings, sprout all over the ductal system and differentiate to become the sites of milk secretion. Here, we review the emerging network of the signaling pathways that connects hormonal stimuli with locally produced signaling molecules and the components of intracellular pathways that regulate alveologenesis and lactation. The powerful tools of mouse genetics have been instrumental in uncovering many of the signaling components involved in controlling alveolar and lactogenic differentiation.