SYMPOSIUM: HORMONAL REGULATION OF MILK SYNTHESIS

Hormones, Mammary Growth, and Lactation: a 41-Year Perspective1

ABSTRACT

When I was a beginning graduate student 41 yr ago it had been established that estrogen caused mammary duct growth; a combination of estrogen and progesterone was required for lobule-alveolar development of the mammary glands; and prolactin and growth hormone were essential for mammary growth. In laboratory species exogenous prolactin, glucocorticoids, and estrogen would initiate secretion of milk provided the mammary glands had a well-developed lobule-alveolar system. It was not known with certainty that progesterone inhibited the process. For some species, prolactin and thyroxine had been shown to stimulate lactation, while glucocorticoids suppressed lactation. Definitive roles for growth hormone and insulin during lactation had not been established. Studies of hormonal control of mammary growth and function in cattle were few. In vitro methods to study hormonal regulation of the mammary glands were in their infancy. Quantitative measures of changes in mammary cell numbers and specific components of milk in response to hormones were rare. The concepts for quantification of hormone concentrations, hormone receptors, growth factors, and binding proteins in blood; hormonal regulation of nutrient partitioning; and hormonally induced mechanisms of action within mammary cells were waiting to be discovered. And eventually they were. However, lest we become too enamored with our current understanding of the hormones that control mammary growth and lactation, it remains a fact that the greatest physiological stimulus for milk yield is pregnancy, not some cocktail of exogenous hormones, growth factors, receptor agonists/ antagonists, or gene therapies. Viva la mom!

(Key words: hormones, mammary growth, lactogenesis, lactation)

Abbreviation key: CBG = corticosteroid binding globulin, IGF-I = insulin-like growth factor, JAK2 = Janus kinase 2, STAT = signal transducers and activators of transcription, TGF-α = transforming growth factor-α, TGF-β = transforming growth factor-β.

INTRODUCTION

A historical perspective of hormonal regulation of mammary growth and function was requested of me— a daunting task when one considers the tens of thousands of publications on this subject, which began before 1900. However, the recent commentary of Professor R. H. Foote (41) rightly encourages us to become better students of history in order to more critically evaluate and understand data currently being generated. So a few historical and classical bits of information with selected references that summarize the state of my knowledge before 1958, the year I entered graduate school, are presented in the first section of this report. Remember, the scientific literature that precedes the advent of computer searches of the literature is extensive. So go to the library and become acquainted with some of the old classics cited in these reviews because they are a basis for our current knowledge of the field. The objective of the remainder of this paper is to provide an overview of some the discoveries made since 1958 regarding interactions among major hormones that control mammary growth and lactation. Selected reviews that will expose the reader to many additional highquality original manuscripts are presented. Many of these discoveries were based on development of new technologies such as in vitro methods to culture mammary slices and cells; radioimmunoassays for measurement of concentrations of hormones in blood and milk; objective methods to quantify mammary cell numbers, chemical components of milk, and number and affinity of hormone receptors; and most recently, development of methods to determine molecular mechanisms of how hormones turn on specific genes.

This presentation is limited to some of the discoveries that occurred during my career that were of greatest interest to me, and, where possible, information for dairy cattle will be presented. Because of this biased presentation, not all significant discoveries made since 1958 will be described. Indeed, some important hormones such as oxytocin, parathyroid hormone, and relaxin will not be discussed. The order of topics, where possible, will be hormonal control of mammogenesis, lactogenesis, and lactation (galactopoiesis).

HORMONES AND MAMMARY FUNCTION

BEFORE 1958

In 1939 Turner (135) summarized many of the classical foundations of knowledge of mammary growth and function. By 1958 it was well established that estrogen stimulated mammary duct growth, and a combination of estrogen and progesterone synergistically stimulated lobule-alveolar development of the mammarygland (25, 39, 87). Prolactin and growth hormone were also mammogenic, and neither estrogen nor progesterone stimulated mammary growth in the absence of secretion of prolactin and growth hormone from the anterior pituitary gland (i.e., in a hypophysectomized animal) (87). In other words, the steroid hormones required prolactin and (or) growth hormone for mammogenic activity. In laboratory species, injections of prolactin, glucocorticoids, and estrogen were discovered to initiate lactation provided the mammary glands had well-developed lobule- alveolar systems (40, 108). In goats, estrogen alone would initiate lactation (91). Exogenous prolactin and growth hormone were observed to stimulate milk synthesis in rabbits and cows, respectively (9, 25). Before 1958 it was well established that experimental reduction in secretion of thyroid hormones reduced secretion of milk (52). Conversely, administration of thyroid hormones or iodinated casein, which possesses thyroxine activity, increased production of milk (10). Because their effects were only temporary, the thyroid hormones never gained acceptability as galactopoietic agents. In contrast to the galactopoietic effects of prolactin, growth hormone, and thyroid hormones, exogenous glucocorticoids generally suppressed an established lactation (25).

HORMONES AND MAMMARY FUNCTION

AFTER 1958

Estrogen

In vitro culture systems were being developed in the1950’s, which permitted direct evaluation of the effectsof hormones on mammary growth and function (34).In 1964, in vitro studies showed that estrogen plusprolactin and growth hormone stimulated mammarygrowth (110). Of further interest to me was the observationthat growth of mammary tissue in vitro was especiallystrong if the medium containing estrogen, prolactin,and growth hormone was supplemented with 5%serum. Subsequently, estrogen was observed to inducesecretion of growth factors from pituitary, kidney, andmammary tumor cells (123). Thus, it was postulated that growth factors secreted from extramammary tissuesinto serum may act via an endocrine mechanismto mediate the mammogenic effects of estrogen. In addition,growth factors secreted locally from mammary tissuemay mediate, via a paracrine or autocrine mechanism,estrogen effects on mammogenesis (31).

Contributing to my understanding of estrogen regulationof mammary growth was the discovery of specificestrogen receptors in mammary tissue (104). Furthermore,evidence in mice showed that estrogen initiallyinduced proliferation of the stroma followed by proliferationof the ductular epithelium (118). In cattle, however,neither adipocytes nor fibroblasts of themammarystroma proliferated in response to estrogen (139).Thus,there are major differences in the hormonal regulationof mammogenesis in rodents and cattle.

Eventually, primary mammary epithelial cells wereembedded in Type I collagen gels, which allowed largeincreases in cell numbers to occur in response to varioushormonal mammogens. However, estrogen alone addedto normal mammary cells failed to stimulate growthin vitro (140). In contrast, later studies showed thatestrogen stimulated epithelial cell growth in mixed culturesof epithelial and stromal cells (90). Furthermore,plastic implants containing estrogen caused local proliferationof the mammary parenchyma in vivo in miceand heifers (60, 119); conversely, implants of antiestrogensinhibited mammary duct growth within circumscribedareas (121). To explain these apparent contradictionsthe concept evolved that estrogens not onlyinteracted with growth factors in serum but also stimulatedsecretion of factor(s) from stromal cells of themammary gland that caused growth of mammary epithelialcells (31, 61). In cattle, stromal cells of the mammarygland secreted insulin-like growth factor (IGFI),a major growth factor implicated in mammogenesis(17).

In addition to IGF-I, other growth factors implicatedin stimulating mammogenesis included epidermalgrowth factor (but not for cattle), fibroblast growth factors,transforming growth factor-α (TGF-α), hepatocytegrowth factor, and macrophage colony stimulatingfactor (8, 31, 60, 61). A plethora of other growth factorsand binding proteins also have been implicated in mammogenesis.But, why are there so many growth factors?Surely they all don’t serve the same function.

Local implants of another growth factor, TGF-β, wereobserved to inhibit mammogenesis in mice (120). Furthercomplicating matters in cattle, however, TGF-βis either stimulatory or inhibitory to mammogenesisdepending on the dose (35).

Receptors for several growth factors have been detectedin mammary tissue, including tissue from cows(44). However, it remains unclear to me where in the cascade the anterior pituitary hormones synergize withestrogen, but one possibility is that the pituitary hormonesinteract in some manner with the growth factorreceptors. Indeed, there is evidence that estrogen interactsin several ways with the IGF signal transductionpathway in breast cancer cells (138). Why not expectpituitary hormones to interact in an analogous fashionin normal mammary cells?

Estrogen was also observed to be involved in initiatinglactation in the periparturient period. Indeed, withimpending parturition concentration of estrogen inblood was the first hormone to increase (126). Estrogenacted in at least two ways to initiate lactation: 1) inseveral species it caused release of prolactin from theanterior pituitary gland into blood (93), which in turn,would initiate lactation; and 2) estrogen increased thenumber of prolactin receptors in mammary cells (117),which is another lactogenic event.

We found that ovariectomy during lactation had noeffect on milk yield in an established lactation (133). Ofcourse subsequent lactations were precluded because ofsterility! Administration of estrogen was observed tosuppress lactation, primarily by interference with themilk-ejection reflex (14). Indeed, estrogens have beenused to suppress lactation in women not wishing tonurse their children.

Progesterone

The early finding that exogenous progesterone synergizedwith estrogen to induce lobule-alveolar growthwas supported by the observation that mammogenesisduring pregnancy in cattle coincided with increased secretionof both estrogen and progesterone (106). Progesteroneinduced DNA synthesis at the end buds andalong the walls of the mammary ducts (12), which werethe sites where progesterone receptors were located(55). Furthermore, estrogen increased the number ofprogesterone receptors (54). These responses provideda basis for my initial understanding of the mechanismwhereby ovarian steroids regulated lobule-alveolargrowth. But, does estrogen directly synergize with progesteroneor its receptor, or is it an estrogen-inducedgrowth factor that synergizes with progesterone to inducelobule-alveolar growth?

Only in rats did injections of estrogen and progesteronestimulate the same quantitative total amount ofmammary development as produced normally by pregnancy,and this was observed before 1958 (74). Laterit was shown that a combination of exogenous estrogenand progesterone achieved only 73% of the developmentobserved during normal pregnancy in cattle (128). Sowhy can’t an appropriate combination of ovarian hormonesadministered to normal heifers induce a quantity of mammary development to match that of a normalpregnancy? Is it a lack of anterior pituitary hormonesor growth factors? What is missing?

Before 1958 progesterone was observed to inhibit histologicalmeasures of lactogenesis. Later it was shownthat injections of progesterone during pregnancy preventednormal initiation of lactose, α-lactalbumin, andcasein synthesis (77, 111, 134). Removal of progesteronevia ovariectomy during pregnancy normally initiatedlactation (83), but if ovariectomy was performed withconcurrent removal of the adrenal or anterior pituitary,lactogenesis did not occur. This reinforced the conceptthat positive (prolactin, adrenal glucocorticoids) as wellas negative (progesterone) factors were involved in lactogenesis.Arapid decline in secretion of progesterone inthe periparturient period in several species, includingcattle, was observed to coincide with initiation of secretionof copious quantities of milk (126). This findingprovided additional correlative evidence of the pivotalrole of progesterone in suppressing lactogenesis.

It was discovered that progesterone blocked lactogenesisin several ways. For example, progesterone suppressedthe ability of prolactin to increase the numberof prolactin receptors in the mammary glands (32). Furthermore,progesterone blocked glucocorticoid receptorsin mammary tissue, which would suppress the lactogenicactivity of the glucocorticoids (22).

One remarkable discovery, made in 1973, showedthat a combination of estradiol-17β and progesteroneadministered for only 7 d, at doses mimicking the highblood concentrations of the two steroids near calving,induced lactation in about 70% of sterile cows treated;the induced lactation was about 70% of normal milkproduction (124). And this report was widely confirmed.Yet today, no combination of exogenous hormonesmatches the consistent milk yields observed with normalpregnancy followed by parturition of cattle. Whynot? Is it associated with failure to obtain fullmammarygland development? Or is the failure associated withfactors missing in the lactogenic milieu?

Although progesterone inhibited initiation of lactation,once lactation became established, administrationof progesterone had no effect on milk yield (58). Theprimary reason progesterone played little or no rolein maintenance of lactation was probably because theprogesterone receptor was not present or at least notexpressed in the mammary glands during this physiologicalstate (55). Moreover, progesterone was observedto have a greater affinity for milk fat than for its ownintracellular receptor, which would further minimizeprogesterone action at the mammary gland during lactation(18).

Prolactin

Prolactin has been the most intensely studied hormonerelated to mammary function. Initial studies in1928 showed that administration of pituitary extractsto rabbits with a well-developed lobule-alveolar mammarysystem promptly initiated copious secretion ofmilk (127), and purification of the extract identifiedthe active molecule to be prolactin (109). Furthermore,injection of prolactin markedly increased developmentof the lobule-alveolar system of the mammary glandsof laboratory species, especially rabbits, and again thiswas discovered before 1958 (86). Later, however, it wasobserved that prolonged elevation of concentrations ofprolactin in serum did not occur during a normal pregnancyin rats and cattle when a large portion of mammarygrowth takes place (2, 96). Thus, it seems unlikelythat secretion of prolactin drives mammary growth duringpregnancy. Yet, as described earlier, we knew thatwithout prolactin and (or) possibly growth hormone, thesteroids, estrogen and progesterone, failed to stimulatemammogenesis. Furthermore, prolactin signaling wasessential for mammogenesis and differentiation of themammary gland during pregnancy, at least in laboratoryspecies (130). More recently it was discovered thatprolactin indirectly (via systemic effects) stimulatedductal side branching and terminal end bud regressionin virgin mice, whereas it directly increased lobulealveolardevelopment at the mammary epithelium duringpregnancy (13).

Recently, some of the mechanisms involved in prolactin-induced mammogenesis have started to become understood,especially for laboratory species. For example,it is now known that prolactin binds to a specific receptoron the surface membrane of the mammary epithelialcell (45). This receptor consisted of an external and aninternal domain (72). When prolactin became boundto its receptor it induced dimerization of the prolactinreceptor, which activated Janus kinase 2 (JAK2) (84).The JAK2, in turn, phosphorylated and activated transcriptionfactors that belong to a family of signal transducersand activators of transcription (STAT). One ofthese factors (STAT5a) in turn promoted expressionof specific genes. In mice, if the genes controlling theprolactin receptor or STAT5a were inactivated, mammarydevelopment failed because of greatly reduceddifferentiation of terminal end buds of the mammaryducts (56, 57). And this failure led to failure of lactation.In addition to future studies of the switches on thepathway that control prolactin regulation of mammogenesis,other mechanistic questions exist. For example,how does prolactin interact with estrogen and progesteroneto stimulate mammogenesis? Because cattle lack typical terminal end buds (60) does this precludea mammogenic effect of prolactin in this species?

Prolactin was discovered to be critically importantfor initiation of lactation in the periparturient periodin several species, including cattle. Indeed in cattle,lactogenesis is the only function of prolactin clearlyestablished to this day. For example, there was a surgein secretion of prolactin several hours before parturition(62). Blockade of this surge with bromocriptine markedlyreduced subsequent milk yield, and exogenous prolactinreversed this effect of bromocriptine (1). In vitrostudies showed that prolactin in association with insulinand cortisol was required to induce secretion of milkproteins (67). Similar to the mechanisms described formammogenesis, binding of prolactin to its receptor wassubsequently found to initiate the lactogenic response.Following binding, a cascade of events was initiatedthat eventually turned on transcription of the genesthat regulate secretion of milk proteins. Again, STAT5 transcription factors appeared to mediate the signalfrom the prolactin receptor to the genes involved inphosphorylation of protein kinases. However, questionsremain. For example, how does progesterone interferewith the ability of prolactin to induce its own receptorduring pregnancy? And where in the cascade does cortisolinteract with prolactin?

Over the past 41 yr the concept has evolved thatprolactin’s importance in maintenance of milk yield dependson the species. In monogastric species, prolactinwas observed to be required for maintenance of milksynthesis. For example in rats, suppression of secretionof prolactin with bromocryptine suppressed secretionof milk (114); conversely, administration of prolactinincreased secretion of milk especially in early lactationand in rabbits (24, 78). However, in cattle and goatsprolactin secretion did not limit secretion of milk. Forexample, prolactin concentration in blood of cows wasonly slightly correlated with yield of milk (75), and supplementalprolactin was without effect on milk yield(101). Furthermore, bromocriptine and cold temperaturesmarkedly reduced secretion of prolactin withoutsuppressing milk yield in cows (98, 100, 125). Curiously,application of the milking stimulus to the teats of cowsacutely released prolactin during early lactation, butas lactation progressed release of prolactin declined(75). Is this latter finding a reflection of changes inphysiological state or diet? And what relevance doesmilking-induced release of prolactin have to intensityof lactation in cattle? Finally, increasing daily lightfrom 8 to 16 h/d in cattle increased concentrations ofprolactin severalfold and also increased milk yield 6 to10% (80, 99). However, there is no unequivocal evidencethat prolactin is responsible for the galactopoietic responsesto photoperiod (131). More recent studies suggested that long-day photoperiods stimulate secretionof IGF-I (27). But, as described later, there is doubt asto the galactopoietic activity of IGF-I. So the riddle ofwhat mediates the galactopoietic responses to long-dayphotoperiods persists.

Growth Hormone

Early reports showed that injection of growth hormoneinto hypophysectomized, adrenalectomized,ovariectomized rats induced growth of the mammaryduct system (87). Much later it was shown in normalheifers that injection of growth hormone caused a largeincrease in mammary parenchymal mass and totalmammary cell numbers (105, 113). A substantial literaturesupported the notion that growth hormone inducedsecretion of IGF-I, from either the liver or from cells inthe mammary stroma, and it may be IGF-I that mediatesthe mammogenic action of growth hormone viaendocrine, paracrine, or autocrine mechanisms (44, 59).

Similar to results from studies with prolactin, concentrationsof growth hormone in serum did not changevery much during a normal gestation when a largeportion of mammary growth occurs (96). Thus, it doesnot seem likely that secretion of growth hormone drivesnormal mammary gland development.

The role of growth hormone during lactogenesis isunclear. In certain strains of hypophysectomized miceexogenous growth hormone was lactogenic (94), but administrationof growth hormone to late-pregnant cowsduring their dry period did not initiate obvious grossanatomical signs of early onset of lactation (122). Furthermore,growth hormone was not lactogenic whenadded to bovine mammary slices cultured in vitro (49).A parturition-induced surge in secretion of growth hormoneoccurred in cattle (62), but the surge was maximalabout the time of delivery of the calf, which was toolate to explain onset of lactation, especially the firststage of lactogenesis. Today it seems reasonable to hypothesizethat growth hormone is not a major playerin onset of lactation in cattle.

The discovery that extracts of anterior pituitarygland and finally of growth hormone’s role in stimulatinglactation in cattle were notable achievements (3, 5,23, 88). This discovery was brought full circle with FDAapproval of commercial use of recombinantly synthesizedgrowth hormone in dairy cattle in 1994. Developmentof recombinant DNA technology allowed productionof the massive amounts of growth hormone requiredfor its commercialization (112). Also critical forthe use of growth hormone as a galactopoietic agent wasthe determination that recombinant growth hormoneincreased milk yield without adverse health implications to either the consumer of milk, the cow itself, orto the environment (4, 68).

Surprisingly, it was observed that growth hormonedid not bind to receptors in the bovine mammary gland(73), although mRNA for the growth hormone receptorwas present in this tissue (47). Moreover, concentrationsof growth hormone in serum did not change inresponse to the milking stimulus, and the decline inserum concentrations of growth hormone with advancinglactation was small (76). So mechanisms of actionof growth hormone were probably located outside themammary gland, and they must be very sensitive tosmall changes in secretion of growth hormone. It waspostulated that growth hormone was involved in coordinatingthe partitioning of nutrients toward the mammarygland during lactation (4). For example, moreenergy from fat is made available to the mammarygland during lactation, especially early lactation. Duringthis physiological state adipocytes become less sensitiveto insulin, and growth hormone receptors locatedon the adipocyte were probably involved in mediationof this action (6).

Growth hormone also binds to receptors on hepatocytes,which stimulated increased secretion of IGF-I.Thus, another concept proposed was that IGF-I bindsto its receptor on mammaryepithelial cells, which mediatesthe action of growth hormone (48). Types I and IIIGF receptors were present in lactating bovine mammarytissue (30). Indeed, arterial administration ofIGF-I close to the mammary gland increased secretionof milk in goats within 2 to 4 h (103). Administrationof IGF-I increased proliferation or survival of mammarycells (20), which has been postulated as a possible mechanismof action for its galactopoietic activity. However,it seems unlikely that a mitogenic response accountsfor the rapid response in milk yield observed with closearterial infusion into the mammary gland. Furthermore,a 24-h infusion of IGF-I was not galactopoieticin goats (102), and others have not found convincingevidence that IGF-I is involved in galactopoiesis (38,115). Collectively, at this stage of our knowledge, itseems a bit unlikely that IGF-I accounts for the galactopoieticactivity of growth hormone.

Another complicating factor in the growth hormonecascade was the discovery of hormone binding proteinsin blood (7). In rodents, about 45% of the growth hormonein blood is bound to a binding protein, whichrestricted growth hormone to the vascular space. Thebinding protein was identical to the extracellular domainof the hepatic growth hormone receptor (81). Agrowth hormone-binding protein has been reported incattle (29), but how does it relate physiologically tomammogenesis, lactogenesis, or maintenance of lactation?

Further complicating my understanding of thegrowth hormone cascade are IGF-I binding proteins, ofwhich there are at least six. These binding proteinsare now postulated to be involved in mediating thebiological activity of growth hormone-induced secretionof IGF-I (19, 20). Such binding proteins were found inserum as well as in interstitial spaces of the mammarygland. Some of the binding proteins inactivated IGF-I,others enhanced activity of IGF-I, and some bindingproteins had biological activity of their own (65). Howthese binding proteins interact to regulate mammogenesisand lactation is currently an area of active study.

Discovery of the chemical structure of the hypothalamicpeptide, growth hormone-releasing hormone, whichcaused release of growth hormone from the anteriorpituitary gland, led to studies showing that the peptidewas as galactopoietic in dairy cattle as growth hormone(28, 36). Will elucidation of hypothalamic regulationof growth hormone secretion lead to new methods ofregulation of mammary function?

Collectively, it appeared that growth hormone, notprolactin, was the primary regulator of lactation in thecow, whereas prolactin, not growth hormone, servedthis function in laboratory species. However, throughappropriate use of inhibitory antibodies against growthhormone and bromocriptine inhibition of prolactin inrats, it has become clear that the individual effects ofgrowth hormone and prolactin could only be observedin the absence of the other (37). Is it possible that effectsof prolactin on lactation in cattle can only be observedin the absence of growth hormone?

Placental Lactogen

In the literature, I witnessed the discovery of placental lactogen in humans (66), a peptide hormone later observed to be synthesized in and secreted from the placenta of many species. Placental lactogen is structurally related to prolactin and (or), depending upon the species, growth hormone (82). In rodents, placental lactogen stimulated mammogenesis by binding primarily to the prolactin receptor (43). In cattle, concentrations of placental lactogen were observed to be very low in maternal serum relative to that in the fetus (137), and administration of placental lactogen had little effect on metabolism of lactating cows (16). Thus, it is not clear to me what role placental lactogen plays in normal mammary physiology of cattle.

Glucocorticoids

Cortisol is the predominant endogenous glucocorticoidin cattle whose major function at the mammarygland is to cause differentiation of the lobule-alveolar system. Indeed, cortisol targeted the endoplasmic reticulumand Golgi apparatus (92). This glucocorticoid-induceddifferentiation was essential to allow prolactinto later induce synthesis of milk proteins.

Injections of glucocorticoids into nonlactating cowswith well-developed lobule-alveolar systems inducedonset of lactation (132), although the quantity of milksubsequently produced was greater if prolactin secretionwas also increased (21). This constituted additionalevidence for synergy among the hormones requiredfor lactogenesis.

As with many other hormones, glucocorticoid concentrationsin blood were quantified during different physiologicalstates of the lactation cycle. In general, glucocorticoidconcentrations in blood remained low for thegreater portion of gestation until just before parturitionwhen they increased to a peak that coincided with deliveryof the offspring (33). This peak occurred too late toaccount for the earliest stage of lactogenesis and maybe associated with the stress of parturition. However,glucocorticoids in serum became bound to a protein,corticosteroid binding globulin (CBG), which inactivatedthe glucocorticoids (46). During the periparturientperiod, CBG decreased and free glucocorticoidsmarkedly increased, which might explain the lactogenicactivity of the glucocorticoids. Later, it was determinedthat glucocorticoids bind to specific receptors in mammarytissue (50), and noncoordinately regulate secretionof α-lactalbumin and β casein (107). Recent evidence(71) suggests that elevated secretion of glucocorticoidsin the periparturient period is associated withsuppression of the immune system, which may contributeto the increased incidence of mastitis and otherdiseases in early lactation. One may expect this areato become more active for research in the future.

Reports before 1958 (116) showed that administrationof adrenocorticotropic hormone, presumably actingvia increased secretion of glucocorticoids, reduced secretionof milk in cattle. Indeed, therapeutic doses ofsynthetic glucocorticoids suppressed milk yields (11).In rats, however, glucocorticoids were strongly galactopoietic(129). Stimuli associated with milking of cowswere found to induce release of glucocorticoids, a patternthat is maintained throughout lactation (76). Incontrast, suckling-induced release of glucocorticoids inrats decreased as lactation progressed (95). If low secretionof glucocorticoids limits the rate of milk secretion,perhaps this explains why exogenous glucocorticoidswere so galactopoietic in rats. In goats and cattle, mammaryuptake and binding of glucocorticoids increasedwith onset of lactation and were positively correlatedwith uptake of glucose into mammary tissue (51, 97).But, what are the subsequent molecular mechanisms,and how might they be related to other hormonallyinduced changes within the mammary epithelial cell?

Thyroid Hormones

Exogenous thyroxine was known to be temporarily galactopoietic well before 1958. The cause of failure to maintain elevated secretion of milk is unknown, although iodine toxicity of the iodinated casein fed has been suggested as a possible cause (J. W. Thomas, 1999, personal communication).

After 1958 it was determined that secretion rates of thyroxine became suppressed as milk yield increased during lactation (85). To me this was unexpected. However, it was discovered that thyroxine in blood had little inherent biological activity and should be viewed as a prohormone that undergoes enzymatic 5′deiodination to form the biologically active hormone triiodothyronine within the thyroid and peripheral tissues. During lactation there was decreased conversion of thyroxine to triiodothyronine in liver and kidneys and increased conversion in the mammary gland (63, 69). Thus, during lactation the mammary gland is in a euthyroid state and the rest of the body is hypothyroid. These conditions would enhance the metabolic priority of the mammary gland. Large quantities of iodine, a major structural component of the thyroid hormones, were lost in milk, which probably contributed to the overall hypothyroid condition of the lactating animal (85).

Insulin

Insulin has little effect on mammogenesis in vivo. However, insulin in supraphysiological doses was observed to be essential for mammogenesis in vitro (42). It is now believed that these high doses of insulin bind to the IGF type I receptor (70), which may mimic the mammogenic effects of IGF-I. This finding may explain older reports that ovarian steroids become mammogenic in hypophysectomized animals concurrently given insulin (64). In other words, the high doses of insulin may substitute for growth hormone-induced secretion of IGF-I and subsequent mammogenesis in the hypophysectomized animal.

Insulin is undoubtedly involved in partitioning of nutrients to the mammary gland during lactation. For example, in lactating rats insulin increased glucose utilization and lipid uptake in the mammary gland (26, 89), whereas adipocytes became insulin resistant (15). Thus, glucose was channeled toward the mammary gland. In contrast, in cattle mammary uptake of glucose, acetate, β-hydroxybutyrate, triglycerides and amino acids was independent of insulin (79). However, in adipose tissue insulin increased utilization of acetate for lipid synthesis while decreasing lipolysis (136). As a result, in cattle insulin was involved in mechanisms partitioning nutrients away from synthesis of milk and toward body tissues. Indeed, insulin concentrations in blood were negatively correlated with milk yield (76). Recently, it has been shown that increasing insulin concentrations in blood, coupled with infusion of glucose to maintain glucose concentrations markedly increased protein concentrations in milk (53). This suggests that it may be possible to manipulate hormones, diet, and genetics to produce milk with a composition directed to the specific needs of the consumer.

CONCLUSION

Before 1958 many, but not all, of the major classical hormones that regulate mammary function had been discovered and catalogued as to their primary function, at least in laboratory species. After 1958 great progress was made in generating new knowledge concerning the cellular and molecular mechanisms involved whereby hormones control mammary function. Commercial application of growth hormone in dairy cows was the most remarkable accomplishment that I witnessed. However, it was based on 57 yr of research and involved an enormous coordinated effort on the part of hundreds of scientists in academic, industrial, and government institutions. Will similar or even greater efforts be required to bring additional scientific breakthroughs in endocrinology to practical use? Probably. I’ve learned to expect the unexpected; so I really don’t know what the next breakthroughs will be specifically, but I am certain there will be stunningly exciting discoveries made. But one prediction I am confident of is that, at least in my lifetime, the greatest physiological stimulus for milk yield will continue to be pregnancy, not some cocktail of exogenous hormones, growth factors, receptor agonists/antagonists, or gene therapies. Viva la mom!

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Source: Michigan State University
Author: Tucker