Physiological Control of Mammary Growth,
Lactogenesis, and Lactation 1
ABST RACT
Research since 1955 that contributed
to understanding mammary function was*
reviewed. Technical breakthroughs in-
cluded methods: 1) to quantify mam-
mary growth; 2) to visualize organelles in
cells; 3) to grow and maintain mammary
tissue in vitro; 4) to quantify hormones in
blood; and 5) to determine binding affini-
ties and numbers of binding sites for hor-
mones. Physiological discoveries included
1) mammary cells accumulate through-
out pregnancy and early lactation; 2) high
doses of estradiol-17/3 and progesterone
induce substantial milk production in a
majority of cattle; 3) estradiol-17/3, pro-
gesterone, prolactin, growth hormone,
and placental lactogen synergize to stimu-
late mammary growth; 4) prolactin and
glucocorticoids induce and progesterone
blocks lactogenesis; 5) milking induces
release of prolactin, glucocorticoids, and
oxytocin into blood; 6 ) g r o w t h hormone
is galactopoietic in ruminants; 7) proges-
terone concentrations in milk may be
used to diagnose pregnancy; and 8) recep-
tors for estrogens, progesterone, gluco-
corticoids, prolactin, placental lactogen,
insulin, and oxytocin are in mammary
tissue. Areas that seem likely to provide
new methods for regulation of milk pro-
duction efficiency are molecular biology,
hormone receptors, harvesting milk,
endocrine-nutrient metabolism, genetic
and environmental basis of hormonal
control of lactation. With continued sup-
port of research, generation of informa-
tion on physiological control of the m a r e -
Received September 4, 1980.
1Michigan Agricultural Experiment Station Journal
Article No. 9623.
1981 J Dairy Sci 64:1403-1421
H. ALLEN T U C K E R
Department of Animal Science
Michigan State University
East Lansing 48824
mary gland and commercial application
of this knowledge should proceed rapidly
in an exciting future!
INTRODUCTION
Function of the mammary gland undergrids
the entire dairy industry, and hormones are the
primary physiological factors that stimulate
mammary growth and initiate and maintain
lactation. This topic is of importance because
manipulation of the endocrine system is a
potential method to improve efficiency of milk
production.
Twenty-five years ago Reece (146) sum-
marized research contributions of m a m m a r y
physiology to the dairy industry. Since then,
progress has continued to be substantial in our
understanding of physiological control of the
mammary gland, but practical application of
some of this new knowledge is just now in for-
mative stages. Thus, greater use of new phy-
siological information to solve farm problems
associated with the mammary gland and milk
production may be anticipated in the future.
This review is to summarize progress in phys-
iology and endocrinology of the mammary
gland and to forecast areas of research that
might provide information for dairymen to
produce milk more efficiently.
TECHNICAL ADVANCES
Quantification of Mammary Development
Before 1953, methods of measuring growth
of the mammary gland were primarily tedious
histometric procedures. A major breakthrough
occurred in 1953 when Kirkham and Turner
(97) introduced use of deoxyribonucleic acid
(DNA), which could be used as a quantitative
measure of total mammary cell numbers. This
technique greatly facilitated investigation of
factors that regulate mammary development (6,
130, 187). Measurements of mammary DNA,
however, do not permit quantification of
1403
1404
individual classes of cells in the mammary
gland. Thus, changes in total mammary DNA
do not reflect necessarily changes in numbers of
secretory cells.
Another technical advance was measure-
ment of incorporation of [a H] thymidine into
DNA of mammary cells. These methods provide
an index of rates of mitotic activity of the vari-
ous cell types in mammary gland (185). Appli-
cation of these techniques has been limited to
studies in common laboratory species or in
vitro experiments.
Electron Microscope
Until 1959, histological observations of
mammary glands were confined to studies by
light microscopy, but in that year Bargmann
and Knopp (11) and Hollmann ( 8 9 ) p u b l i s h e d
papers describing electron microscopy of mam-
mary glands. This powerful technique revealed
the basic organization of organelles within
mammary epithelial cells and contributed sig-
nificantly to our current understanding of
effects of hormones on differentiation of
mammary epithelium (90). Although ultra-
structural evaluation does not provide a direct
measure of total mammary cells or of cellular
organdies, it offers advantages over methods
based on total DNA content. Namely, cell
types within the tissue can be distinguished and
cytological characteristics per cell quantified.
Perhaps the best way to estimate mammary
development is to combine DNA and quantita-
tive histometric measures (130).
Tissue Culture
In 1957, Elias (53) described a procedure
which permitted cultivation of mammary tissue
explants in serum-free medium. This technique
was applied to mammary tissues of a number of
species including cattle (33). By these in vitro
techniques, specific direct effects of a hormone
on mammary gland tissue can be elucidated,
uncomplicated by other hormones or extra-
mammary factors as with in vivo models (61).
A disadvantage of these in vitro techniques is
that the useful life of an explant usually does
not persist beyond 5 days. Nevertheless, in vitro
techniques are valuable tools for elucidating
hormonal control of mammary gland, especially
during lactogenesis. Cultivation of dissociated
epithelial cells on floating collagen gels is a
Journal of Dairy Science Vol. 64, No. 6, 1981
TUCKER
recent development which may be an excel-
lent technique to study hormonal control of
mammary epithelium for prolonged time (55).
Another promising approach for study of
mammary tissue involves use of athymic nude
mice. Athymic nude mice are immunologically
incompetent, and thus transplants of tissue
from heterospecies will not be rejected. Indeed,
transplantation of cow mammary tissue into
athymic nude mice has been accomplished
(204). These xenographs grew and synthesized
a-lactalbumin in response to hormone treat-
ment.
Radioimmunoassay
Much information concerning hormonal
regulation of mammary glands before 1956 was
gained by classical experimental approaches of
endocrine gland ablation followed by appro-
priate hormone replacement therapy (146).
Measurement of hormone concentrations in
various endocrine glands also contributed to
our knowledge of endocrine control of the
mammary gland. Most of these measures were
based on bioassay techniques. It was not until
1960, when Yalow and Berson (205) developed
radioimmunoassay techniques, that concentra-
tion of hormones in blood could be measured
reliably. This technique led to an explosion of
information concerning hormonal regulation of
the mammary gland. Radioimmunoassays have
been developed for most hormones affecting
the mammary gland, and measurements of hor-
mones were in blood collected in a wide variety
of physiological and experimental conditions.
As a note of precaution, however, quantifica-
tion of a hormone in blood is a reflection of the
balance between its secretion and clearance
rates. Therefore, concentration of a hormone in
blood does not represent necessarily utilization
by target tissue. In addition, immunological
measurements of hormones do not represent
necessarily biological activity. Thus, concentra-
tions of hormones in blood should be inter-
preted in relation to the functional state of the
animal.
Hormone Binding
For hormones to exert their action, they
usually bind to specific high affinity receptors
in the mammary cell. As a consequence of
binding, a casade of events is set in motion that
 PHYSIOLOGICALCONTROL- 75TH ANNIVERSARYISSUE
eventually causes physiological response. Devel-
opment of methods to radioactively label hor-
mones with high specific activity permitted
initiation of investigation in this area. A num-
ber of studies in a variety of tissues, including
mammary tissue, suggest that steroid hormones
readily pass through plasma membrane and
bind to cytoplasmic receptors (73). Thereafter
the steroid hormone-receptor complexes move
to the nucleus where they interact with specific
nuclear acceptor sites to alter transcription of
specific genes (73). In contrast to steroids, pep-
tide hormones bind to specific receptors on
plasma membrane, thereby activating adenyl
cyclase and decreasing cyclic adenosine mono-
phosphate (cAMP)-phosphodiesterase (73). This
leads to increased cAMP, activation of cAMP-
dependent kinases, and phosphorylation of
many proteins. There is little evidence, how-
ever, that these processes directly increase
ribonucleic acid or protein synthesis. Details
of hormone binding to mammary tissue and
subsequent amplification steps are understood
only sketchily, but these studies could lead to
development of additional methods for regu-
lation of the mammary cell.
PHYSIOLOGICAL DISCOVERIES
Mammary Growth
The number of cells available for synthesis
of milk is one of the primary determinants of
milk production. Within the past 25 yr simple
correlations measured between total mammary
DNA and milk yield ranged from .50 to .85
(186). Thus, studies of control of mammary
growth may lead to new methods of enhancing
amount and efficiency of milk production. For
example, most often dairy c o w s are selected to
become parents after initial production records
become available. Selection could be early if
criteria existed for accurately predicting subse-
quent milk production. Neither subjective pal-
pation scores (177) nor quantitative measures
of DNA content of mammary glands (190) have
sufficiently high correlation coefficients with
subsequent milk yield to be reliable means of
predicting future milk production. This remains
a problem.
Prepubertal heifers fed large or restricted
quantities of energy produce substantially Iess
milk than heifers fed recommended allowances
(147, 158, 172). High energy rations fed before
1405
puberty reduce subsequent mammary develop-
ment, but high energy rations after puberty
have no effect on subsequent mammary de-
velopment (159). Hormonal implications be-
tween energy intake and mammary develop-
ment need to be established.
In 1949, Cowie (39) showed that mammary
glands begin to grow allometrically before
puberty. Subsequently, allometric growth con-
tinues for several estrous cycles, then returns
to isometric rates until conception (187). Be-
fore mammary DNA measurements, it was
believed that mammary development was com-
pleted by mid-pregnancy. But when DNA was
quantified in mammary glands, it was observed
that mammary cell numbers accumulate lin-
early throughout gestation (175, 187). Mam-
mary growth continues into early lactation in
many species, including goats (8), but not sheep
(7). Moreover, increasing the milking stimulus
during early lactation in rats increases mam-
mary development to the point where the total
amount of mammary development produced
during lactation may exceed that of pregnancy
(186). Mammary ceils formed during lactation
acquire their fully functional enzymatic com-
plement shortly after formation (10). Early
phases of concurrent pregnancy and lactation
do not alter mammary development, but later
marked reductions occur in mammary develop-
ment and lactational performance (138). Causes
of pregnancy-induced reductions in milk yield
are not clear, although enhanced secretion of
estrogens and progesterone and increased fetal
competition for nutrients have been suggested.
Just before parturition mammary alveolar
epithelial cells are characterized by irregularly
shaped nuclei, scant rough endoplasmic retic-
ulum, ill-defined Golgi membranes, few mito-
chrondria, and a high nuclear to cytoplasmic
ratio (84). During the periparturient period,
hormonal signals caused marked differentiation
of these cells such that the rough endoplasmic
reticulum proliferates; Golgi membranes hyper-
trophy, orient towards the cell apex, and con-
tain many protein-filled vesicles; mitochondria
increase in number; and fat globules ~nd casein
micelles proliferate within the cytoplasm;
nuclear to cytoplasmic ratios are reduced; and
nucleus and ergastoplasm assume a basal
orientation in cells (90). Volume of the cells in-
creases markedly. Moreover, prepartum re-
moval of milk from udder halves hastens differ-
Journal of Dairy Science Vol. 64, No. 6, 1981
 1406 TUCKER
entiation of mammary epithelial cells (4) and
explains, in part, why prepartum milking initia-
tes lactation. Presumably stimulatory effects of
prepartum milking would not be exerted with-
out involvement of the endocrine system. Half-
udders not milked prepartum were much less
differentiated than half-udders milked prepar-
turn (4), but mechanism of this local effect on
mammary gland is unknown.
Involution of the mammary gland quickly
follows failure to remove milk at regular inter-
vals. For example, following cessation of milk-
ing, mammary cells become engorged with secre-
tory products, and engorgement is followed
by resorption of accumulated milk (91, 106).
Involution is characterized by decreased meta-
bolic activity, size of alveoli, and number of
alveoli and alveolar epithelial cells (91). En-
zymes in lysosomes are released, and they
digest epithelial cells (86). Connective tissues
become more obvious histologically, but
absolute amounts decrease (137). Myoepithe-
lial cells are not lost during involution and ap-
pear to hold surviving epithelial cells together
(91).
It has been known for many years that a
period of nonlactation (dry period) between
successive lactations is essential for maximal
production of milk. During the past quarter
century information was obtained on cellular
changes during the dry period. For example,
concurrent pregnancy during this interval re-
tards, but does not completely prevent, cell
losses during this interval (138). If the dry
period is too short, mammary growth is re-
stricted during early phases of subsequent
lactation and milk yields are reduced (138,
174).
Changes in hormone secretion and binding
of hormones cause changes in total mammary
cell numbers, differentiation, and involution of
mammary cells during various physiological
epochs of an animal. Before 1956, many of the
basic hormonal requirements for mammary
development were established (146). For exam-
ple, estrogens caused mammary duct growth
whereas progestins, especially when combined
with estrogens, promoted lobule-alveolar de-
velopment. However, these steroids were com-
pletely ineffective in stimulating mammary
development in hypophysectomized animals. A
number of studies implicated anterior pituitary
hormones in control of mammary growth
Journal of Dairy Science Vol. 64, No. 6, 1981
(197), and these endeavors were culminated by
Lyons (115) in a series of classical experiments
that showed that in ovariectomized-adrenalec-
tomized-hypophysectomized rats, estrogens and
growth hormone promote mammary duct
growth, whereas progestins and prolactin stim-
ulate lobule-alveolar development. Maximal
mammary development was achieved with these
four hormones plus glucocorticoids (115).
A number of studies were published (6,124,
171) in which the goal was to obtain maximal
mammary development following administra-
tion of estrogens and progestins. In 1957,
Benson et al. (14) observed that absolute quan-
tities of progesterone and estrogen are of
greater importance than ratios of these hor-
mones in stimulating lobule-alveolar develop-
ment of the gland. But to my knowledge, only
in rats has a combination of exogenous estrogen
and progesterone produced total mammary
development equivalent to that during a normal
pregnancy (127). Numerous investigators have
tried to cause mammary development and
initiate lactation in dairy cows with hormones.
In most experiments estrogens have been tested
alone or in combination with progesterone,
but variability in total mammary development
and in subsequent milk yield was great (124).
Frequently milk yields were substantially lower
than quantities expected following a normal
pregnancy. The most exciting breakthrough in
this research occurred in 1973 when Smith and
Schanbacher (165) initiated lactation in 60 to
70% of barren cows with a combination of .025
mg/kg body weight of estradiol-17/3 and .063
mg/kg body weight of progesterone injected at
12-h intervals for only 7 days. More recently,
the success rate (daily yield greater than 9 kg)
was increased to 100% when reserpine (a tran-
quilizing drug that stimulates prolactin secre-
tion) was added to the steroid combination
(32).
Other approaches to study hormonal regula-
tion of mammary growth related changes in
concentrations of hormones in blood to
changes in mammary development. Generally
estradiol and progesterone secretion is asyn-
chronous during the estrous cycle, whereas
during pregnancy both hormones increased
simultaneously (25). These differences in secre-
tion pattern may account, at least partially, for
failure of the mammary gland to maintain allo-
metric growth before conception, whereas
 PHYSIOLOGICAL CONTROL
during pregnancy continuous allometric growth
Occurs.
Great strides were made in elucidation of
mechanisms whereby ovarian steroids affect
mammary growth. For example, estrogen and
progesterone reduce time for mammary DNA
synthesis (23). Moreover, estradiol-17/~ and
progesterone stimulate incorporation of [3H]
thymidine into DNA in terminal end buds of
mammary gland, whereas only progesterone
induces DNA synthesis along ductular walls
(24). Later Puca and Bresciani (144) found
specific estrogen receptors in mammary tissue.
Muldoon (129) showed that estrogen receptors
first appear in mouse mammary tissue near
puberty and that these receptors increase pro-
portionately to increasing weight of the tissue.
Moreover, estradiol-17/3 induced synthesis of
estrogen receptors in mature but not in im-
mature animals (129). As gestation advances,
estrogen receptors are converted progressively
from 4S to 8S form so that during lactation 8S
form predominates (129). Prolactin induces this
shift from 4S to 8S form. Both forms of the
receptor bind estradiol with equal affinity, and
each form is translocated to the nucleus of the
mammary cell (129). It remains to be deter-
mined how these changes in physicochemical
properties of receptor alter function of mam-
mary gland.
As might be expected, progesterone is bound
to its receptor in mammary tissue of virgins and
during pregnancy, but the receptor disappears
during lactation and reappears during involu-
tion (81). Thus, steroid receptors in mammary
tissue coincide with mammary growth respon-
ses. Absence of progesterone receptor during
lactation also could explain why administration
of progesterone during this physiological state
does not affect synthesis of milk (87).
As previously implied, pituitary hormones
are also critically important for mammary
development. For example, Talwalker and
Meites (178) restored mammary development
in hypophysectomized rats with exogenous pro-
lactin and growth hormone. Steroid replace-
ment therapy alone was ineffective in hypo-
physectomized animals. Cowie et al. (43)
showed in hypophysectomized, ovariectomized
goats that a combination of estrogen, proges-
terone, prolactin, growth hormone, and adreno-
corticotropin was required for alveolar develop-
ment comparable to mid-pregnancy.
- 75TH ANNIVERSARY ISSUE 1407
During the past 25 yr the important role of
hypothalamic hormones in regulation of
anterior pituitary function was established
firmly (35). Prolactin secretion is inhibited
tonically as a result of a factor(s) secreted from
the hypothalamus into portal vessels of the
pituitary stalk and delivered to the anterior
pituitary (117, 170). When the anterior pitui-
tary is transplanted to a site remote from the
hypothalamus, prolactin secretion from the
transplant is stin~ulated markedly (125). When
this was done in intact virgin rats, mammary
development was stimulated markedly, but if
the transplants were in ovariectomized rats,
enhancement of mammary development was re-
duced (164). The conclusion is that under nor-
mal physiological conditions ovarian hormones
synergize with pituitary hormones to produce
mammary development.
Before 1955 researchers demonstrated that
hypophysectomy during pregnancy does not
affect mammary cell numbers (108, 141). This
raised the possibility that the placenta is an
important source of mammogenic hormones.
Indeed, a hormone unique to placenta that pos-
sesses structural and immunological homologies
with prolactin and growth hormone has been
identified in a variety o f species (96). Injection
of saline extracts of rat placentas into hypo-
physectomized, ovariectomized rats stimulates
considerable lobule-alveolar development (145).
In most species, secretion of placental lacto-
gen commences about midpregnancy and re-
mains elevated until parturition. Thus, it is
likely that placental lactogen synergizes with
estrogens, progestins, prolactin, and growth
hormone to cause mammary development
during normal gestation. Increased secretion of
placental lactogen may account for greater
mammary development as number and weights
of placentas increase in several species, inclu-
ding goats (82). However, there is controversy
as to whether placental lactogen exists in signif-
icant amounts in cattle. For example, based on
radioreceptor assays cows did not possess pla-
cental lactogen (96), but others purified and
characterized a bovine placental lactogen in sera
of cattle after midpregnancy (18, 20).
In addition to providing placental lactogen,
the placenta is an important source of estrogens
and in some species, but not cattle, of proges-
terone (58, 181). There is evidence to suggest
that fetal placentas are primary sources of
Journal of Dairy Science Vol. 64, No. 6, 1981
1408 TUCKER
mammotrophic hormones after mid-gestation
(48). Subsequently, Adkinson et al. (1) showed
that sire of fetus affects subsequent milk yields.
Presumably this effect is transmitted through
placental hormones.
Although administration of prolactin and
growth hormone will stimulate mammary
growth, these hormones do not function neces-
sarily in this role endogenously. Sharp increases
in serum prolactin concentrations during pro-
estrus precede increased mammary growth
during estrus in rats (5), but the homologous
rise in prolactin at estrus in heifers is much less
(152). Thus, it has not been demonstrated con-
elusively that prolactin is the agent that causes
development of mammary epithelium during
the estrous cycle of heifers. Moreover, prolac-
tin secretion in many species is not elevated
during the greater portion of gestation (5,136).
In addition, the number of prolactin receptors
per mammary cell is suppressed during gesta-
tion in rats and mice (88,154), whereas Djiane
et al. (51) showed that prolactin binding to
mammary tissue increases three- to fourfold
during pregnancy in rabbits. These species dif-
ferences may be associated with differences in
secretion rates of placental lactogen; i.e.,
rabbits have no placental lactogen, but rats and
mice have large quantities. Therefore, occu-
pancy of the prolactin receptor by placental
lactogen in rats and mice may mask measure-
ment of prolactin binding (132). In any event,
roles that prolactin and prolactin binding play
in normal mammary growth of gestation, espe-
cially in dairy cattle remain to be established.
Although growth hormone may increase in
some species during the proestrus-estrus phase
of the estrous cycle, it does not change during
the greater portion of gestation (136). Perhaps
the best theory concerning roles of prolactin
and growth hormone in normal mammary gland
development is that both hormones are re-
quired, but it is improbable that their concen-
trations limit the process.
Recently, data were published that strongly
suggest that hypothyroidism in rats retards
ductal and lobule-alveolar growth of the mam-
mary gland whereas supplemental thyroid hor-
mone administration restores growth (202).
Other investigators also observed that thyroid
hormones are essential for maximum prolifera-
tion of mammary gland in laboratory species
(6). It would seem prudent, therefore, to inves-
Journal of Dairy Science Vol. 64, No. 6, 1981
tigate whether thyroid hormones are rate-
limiting to maximal mammary development in
dairy animals.
The role of insulin in control of mammo-
genesis received considerable study. Insulin is
required to maintain mammary tissue cultured
in vitro (61). Mammary cells are resistant (in
terms of DNA synthesis and a variety of other
characteristics) to insulin before conception,
become sensitive to insulin during gestation and
lactation, then revert to insulin insensitivity
again during involution (134). Although insulin
stimulates mitosis of mammary gland in vitro,
it is not absolutely essential for mammary
growth in vivo. For example, severely diabetic
mice treated with estrogen and progesterone
develop extensive mammary lobule-alveolar
structures (182). Nonetheless, insulin syner-
gized with exogenous estrogen and progester-
one to promote increased mammary develop-
ment (104). Since insulin decreases in serum
during gestation, it seems unlikely that insulin
is rate-limiting to normal mammary develop-
ment in cattle (70).
Relaxin is another hormone that by itself
has little mammogenic activity but is capable of
synergizing with anterior pituitary and ovarian
steroid hormones to stimulate mammogenesis
in laboratory species (78). However, the exact
role of relaxin in normal mammary develop-
ment is yet to be established.
Lactogenesis
Lactogenesis consists of a series of events in
the differentiation process whereby mammary
cells are converted from a nonsecretory to a
secretory state. The process has been defined,
for convenience, as a two-stage mechanism
(59, 80). The first stage consists of cytologic
and enzymatic differentiation of alveolar cells
and coincides with limited milk secretion
before parturition. The second stage consists
of copious secretion of all products of milk and
begins approximately 0 to 4 days before
parturition and extends through a few days
postpartum.
Before 1956 it was established that prolac-
tin, adrenocorticotropin (via stimulation of
secretion of glucocorticoids), and estrogens
initiated lactation and that progesterone inhib-
ited lactogenesis (146). During the past 25 yr
many papers have filled in details of lacto-
genesis (56,189).
 PHYSIOLOGICAL CONTROL - 75TH ANNIVERSARY ISSUE
Perhaps one of the most dramatic pieces of
evidence demonstrating that prolactin plays a
major role in lactogenesis came from a study by
Cowie (40) in a hypophysectomized goat.
Hypophysectomy caused a rapid decline in
daily milk yield in this goat. Administration of
a glucocorticoid, triiodothyronine, and growth
hormone restored lactation to approximately
28% of normal, but when prolactin was added
to the combination, milk yields were restored
completely.
With the advent of radioimmunoassays, it
has been observed that secretion of prolactin in-
creases sharply just prior to parturition, and
blockage of this surge with ergot alkaloid drugs
reduces but does not prevent completely sub-
sequent lactation (155). If cows are given the
ergot drug plus exogenous prolactin in quanti-
ties to mimic the periparturient surge of pro-
lactin, subsequent lactation is not reduced (2).
These data, therefore, support the concept that
prolactin is essential for full lactogenesis in
cattle.
Many discoveries in the past quarter century
of effects of prolactin on the mammary cell
suggest that this hormone regulates milk pro-
tein synthesis. For example, prolactin enhances
rates of casein and 0z-lactalbumin synthesis in
rabbit and bovine mammary tissue explants
(49, 66). In addition prolactin induces a 10
times increase in accumulation of casein mes-
senger ribonucleic acid (mRNA), a 2 to 4 times
increase in rate of casein mRNA transcription
and a 17 to 25 times increase in the half life of
casein m R N A in mammary tissue explants from
mid-pregnant rats (72, 123, 151). Moreover,
prolactin and glucocorticoids stabilize casein
mRNA in mammary tissue from rabbits (93).
Prolactin receptors in mammary gland increase
in parallel with increased secretion of prolactin
in the periparturient period coincident with
secretion of copious quantities of milk (51).
Collectively, the above data support the con-
cept that prolactin plays a major role in the
second stage of lactogenesis. Prolactin, how-
ever, is by no means the only hormone in-
volved. For example, inhibition of prolactin
secretion to practically undetectable levels with
an ergot alkaloid only suppresses milk yield
approximately 11 kg per day (2). Thus, other
hormones, such as adrenocorticotropin, growth
hormone, placental lactogen, or thyroid hor-
mones, may synergize with the low prolactin
1409
in ergot-treated animals and may be responsible
for substantial secretion of milk postpartum.
Failure of ergot alkaloids to suppress com-
pletely postpartum secretion of milk appears to
be limited to ruminants because treatment of
nonruminants with these drugs has led invari-
ably to complete inhibition of lactogenesis
(189).
The role of growth hormone in lactogenesis
appears to be one of synergism with prolactin
and adrenocorticotropin. Although a surge in
secretion of growth hormone occurs coincident
with parturition (94), the importance of this
release during lactogenesis remains to be
elucidated.
The precise role of placental lactogen in
lactogenesis is not known, but it has been sug-
gested that it may function in the initial phase
of lactogenesis (52).
In the past quarter century the role of
adrenal glucocorticoids in lactogenesis has
become more nearly clear. For example, glu-
cocorticoids given to cattle with well-developed
mammary glands quickly initiate copious secre-
tion of milk (191). In the alveolar cell cortisol
induces differentiation of the rough endo-
plasmic reticulum and Golgi apparatus (126).
Moreover, adrenalectomy blocks synthesis of
casein-like proteins and RNA, which normally
occurs during lactogenesis (45). Adrenalectomy
markedly inhibits, whereas cortisol stimulates,
synthesis of casein mRNA (65). These observa-
tions support the concept that adrenal gluco-
corticoids are essential for full lactogenesis.
Similar to other hormones, glucocorticoids
bind to specific receptors within the mammary
cell. In mice there is a 3 time increase in num-
ber of cortisol receptors in mammary gland
during the second half of pregnancy (31). More-
over, progesterone blocks binding of cortisol
effectively at the glucocorticoid binding site
(27). This may explain, at least in part, how
progesterone is able to inhibit lactogenesis.
Data in cattle (168) show that glucocorti-
cold secretion increases markedly just prior to
or coincident with parturition. Whether this
surge is essential for lactogenesis or merely is
associated with stress of parturition is un-
known.
Another factor associated with glucocorti-
colds is corticoid binding globulin (CBG), a
blood protein that binds glucocorticoids and
renders them biologically inactive. This pro-
Journal of Dairy Science Vol. 64, No. 6, 1981
1410
tein decreases during the periparturient period
of rats, thereby effectively increasing concen-
tration of free corticosteroids (64). Whether a
similar phenomenon occurs in dairy animals
remains unknown.
Of all the hormones measured in blood of
periparturient cattle the first detectable changes
prior to parturition are increased secretion of
estrone and estradiol-17/3 (168). Concentrations
of these estrogens begin to increase about 1
mo before expected parturition, reach their
zenith within 2 days of parturition, then
rapidly decline. The precise role of estrogens
in lactogenesis has not been determined, but
exogenous estrogens induce secretion of milk in
a variety of species, including cattle, provided
the animals possess well-developed mammary
glands (124). Until recently there was no evi-
dence to suggest that estrogens directly affect
mammary gland. However, estradiol-173 in-
duced secretion of casein in mouse mammary
tissue cultured in vitro (19). Furthermore, we
observed similar effects on induction of a-
lactalbumin secretion in bovine mammary tis-
sue cultured in vitro (66). Although induced
secretion of ~-lactalbumin was only 31% of that
obtained with prolactin alone, the two hor-
mones readily synergized to induce secretion
of aqactalbumin. Estrogens and glucocorticoids
increase the numbers of prolactin receptors
(153, 162). Perhaps these mechanisms explain
synergistic effects among prolactin, glucocorti-
coids, and estrogens on stimulating lactogenesis.
Among hormones studied during the peri-
parturient period, the role of progesterone is
best understood; it inhibits lactogenesis. Based
on histological examination of the tissue before
1956, exogenous progesterone was known to
inhibit mammary secretion. Since that time,
several specific sites of inhibition were estab-
lished. For example, progesterone suppresses
normal periparturient onset of synthesis of lac-
tose, a-lactalbumin, and casein ( 1 0 3 , 1 5 1 , 1 9 5 )
as well as prolactin-induced synthesis of these
milk constituents (66, 151). Conversely, if
progesterone concentrations in serum are re-
duced during the periparturient period, there
is a sharp increase in synthesis of mammary
enzymes and milk proteins (114, 131). Further-
more, there is a marked decrease in progester-
one secretion 1 to 2 days before parturition,
which coincides with onset of lactation (168).
Progesterone binds to a progesterone recep-
Journal of Dairy Science Vol. 64, No. 6, 1981
TUCKER
tor in mammary tissue (120), but it also com-
petes with glucocorticoids for binding on the
glucocorticoid receptor (34). Perhaps the high
progesterone normally secreted during gestation
occupies glucocorticoid binding sites and pre-
vents glucocorticoids from initiating lactation
during the greater part of gestation. Progester-
one also blocks the ability of prolactin to in-
duce synthesis of prolactin receptors (50),
another anti-lactogenic effect.
ProstagIandin F2ct is luteolytic in several
species, including cattle (25). In addition, exo-
genous prostaglandin F2a initiates lactation in
several species (105). Moreover, prostaglandin
F2a stimulates rapid release of several lacto-
genie hormones, including prolactin, growth
hormone, and glucocorticoids (111). Therefore,
prostaglandin F2a should be considered as a
factor in the complex which initiates lactation.
Lactation
By 1956, it was well-established that oxyto-
cin facilitated milk removal; that hypophysec-
tomy reduced milk production; that prolactin,
adrenal glucocorticoids, and thyroid hormones
were essential for lactation; that exogenous
insulin inhibited milk production; and that
removal of the ovaries did not affect concurrent
milk secretion. Folley and Young (60) correct-
ly proposed that lactation was controlled by a
hormonal complex.
Within the past quarter century much addi-
tional information was generated concerning
the role of prolactin in maintenance of lacta-
tion. For example, in rabbits, but not other
species, prolactin alone will restore milk yields
to normal following hypophysectomy (41).
Exogenous prolactin shortens the time required
for the mammary gland to refill in rats (71). In
addition, milking causes a sharp increase _in_
concentrations of prolactin in serum (188);
however, as stage of lactation progresses quanti-
ties of prolactin released during milking grad-
ually diminish (98). Prolactin concentrations in
blood are positively correlated with yield of
milk in cattle, although coefficients are low
(98). Moreover, increased clearance and secre-
tion rates of prolactin are greater in early than
late lactation and are associated positively with
increased milk production in dairy cattle (3).
Conversely, administration of prolactin to
sheep does not enhance lactational performance
(47). Sufficient amounts of highly purified pro-
 PHYSIOLOGICAL CONTROL - 75TH ANNIVERSARY ISSUE
lactin have not been available to test prolactin's
ability to stimulate milk yield in dairy cows.
Recently, we observed that increasing dura-
tion of light from 8 to 16 h daily increases
prolactin secretion markedly (107) and also en-
hances milk production approximately 10%
(142). However, it is not clear if photoperiod-
enhanced secretion of prolactin is responsible
for increased production of milk, because am-
bient temperatures below freezing block the
ability of light to stimulate prolactin secretion
(143), but milk production still was increased
by 16 h of light despite many days when tem-
peratures were below freezing.
Mammary uptake of prolactin from blood is
greatest just after it is released from the anter-
ior pituitary. Moreover, uptake of prolactin is
greater in early lactation when milk yields are
largest (13). Specific, high affinity receptors
of prolactin are detectable in mammary tissue
from lactating animals (62), and binding of pro-
lactin to these receptors follows its uptake from
blood. Numbers of prolactin receptors increase
markedly following parturition (88) coincident
with increased lactational performance. More-
over, administration of antisera to the prolactin
receptor inhibits casein synthesis (163). Thus,
binding of prolactin to its receptor is important
for biological function of the mammary gland
at the cellular level. Prolactin probably is incor-
porated into the mammary cell (133) and is
secreted into milk approximately in proportion
to its concentration in blood (118).
A variety of drugs and natural biological fac-
tors increase secretion of prolactin, but to my
knowledge only reserpine and thyrotropin re-
leasing hormone (TRH) have been tested for
galactopoietic activity in cattle (32, 37). As
previously described, reserpine combined with
lactogenic doses of estradiol-17/~ and proges-
terone increases milk yields in barren cattle.
The increments in milk yield are small in lacta-
ting cows given TRH, and other galactopoietic
hormones [i.e., growth hormone and thyro-
tropin (and thyroxine)] in addition to prolactin
are released by TRH (38). To summarize, it has
not been possible to associate enhanced secre-
tion of prolactin during lactation specifically
with increased milk yield.
Several drugs and naturally occurring bio-
logical compounds reduce secretion of prolac-
tin. In nonruminant species these compounds
also suppress lactational performance. The most
1411
commonly tested compounds are dopamine and
various ergot alkaloids, which are dopamine
agonists. Surprisingly, in ruminants suppression
of prolactin secretion during an established
lactation does not affect milk production
(166). Thus, prolactin may be important but
perhaps not normally rate limiting for mainten-
ance of lactation in these species. However, the
role of prolactin in maintenance of secretion of
milk in ruminants is still not determined; per-
haps in the next quarter century this problem
will be resolved.
Growth hormone is galactopoietic in rumi-
nants. For example, Machlin (116) found that
growth hormone injected three times per week
markedly enhanced milk production of dairy
cows. Concentrations of growth hormone do
not change during milking in cows (188), al-
though it is released in goats during milking
(79). Concentrations of growth hormone in
serum following administration of TRH are sub-
stantially greater in early than late lactation
(199), which coincides with the highest rate of
secretion of milk. It seems likely that develop-
ment of methods to stimulate secretion of
growth hormone will increase yields of milk.
Relatively little research effort is directed
toward control of growth hormone secretion.
In the past 25 yr it was established that
adrenalectomy reduces milk yields, enzymatic
function, and casein m R N A synthesis of mam-
mary glands of laboratory species (9, 100,
179) and that supplementation with glucocorti-
coids retards the normal decline in milk yield
over time (180). The role of glucocorticoids is
less clear in ruminants, however. For example,
exogenous adrenocorticotropin or glucocorti-
coids given in therapeutic doses markedly sup-
pressed milk yields (22, 160). More recently,
however, when smaller doses of glucocorticoids
were tested, effects on milk production were
conflicting; in one study milk yields were not
affected (83) whereas in another yields were
increased (176). Glucocorticoids are released
in response to milking stimuli (167), and stage
of lactation does not affect the quantity re-
leased (99). Also, glucocorticoids are taken up
from the blood at milking (139), and they be-
come bound to specific receptors in mammary
tissue (68). The number of binding sites in
mammary tissue from lactating cows is about
four times greater than the number in nonlactat-
ing cows, and glucocorticoid binding is correlat-
Journal of Dairy Science Vol. 64, No. 6, 1981
1412 TUCKER
ed with glucose uptake into mammary tissue
(69). Thus, glucocorticoids are associated with
lactation, but there is little evidence they nor-
mally limit milk production in ruminants.
Thyroid active compounds were used com-
mercially to stimulate lactation before 1956.
Many of the advantages and limitations of this
practice were elucidated (16). Thyroprotein
administered throughout lactation did not stim-
ulate overall milk production (128, 157).
Several methods were developed to measure
thyroxine secretion rates (196). But questions
of reliability were noted, especially in situations
where iodine may be in limited supply, for
example, during lactation (148, 173). Use of a
"direct o u t p u t " method, which is applicable to
conditions where iodine may be in limited sup-
ply, suggested that rates of thyroid secretion in
rats were reduced during lactation (110). Sup-
plemental dietary iodine does not affect con-
centrations of serum thyroxine or tri-iodo-
thyronine in cattle (36), and these indices of
thyroid function also are related inversely to
the quantities of milk produced (110, 198).
Mechanisms whereby thyroid hormones affect
mammary function during lactation have re-
ceived relatively little attention, although it
appears that thyroprotein feeding, which in-
creases serum thyroxine, has no effect on con-
centrations of prolactin, growth hormone, or
total glucocorticoids in serum (161). Few
studies have reported direct effects of thyroid
hormones on mammary secretory cells, al-
though there is evidence that thyroid hor-
mones may affect DNA synthesis and differen-
tiation of mouse mammary tissues (201).
Calcitonin, another hormone from the thy-
roid gland, which was discovered in the past 25
yr, plays an important role in prevention of
increases in calcium and phosphorus of blood
serum during lactation (184). Calcitonin con-
centrations in blood serum of lactating rats are
greater than concentrations in nonlactating
animals (183), and suppression of calcium and
phosphorus concentrations in serum are
achieved more easily in lactating than in non-
lactating rats (184). Concentrations of calci-
tonin in blood of cows at parturition have
increased (26), but whether this hormone im-
portantly limits production of milk is unclear.
Parathyroidectomy reduces milk produc-
tion (200) and concentrations of calcium in
blood serum during lactation (63). Conversely,
Journal of Dairy Science Vol. 64, No. 6, 1981
administration of parathyroid hormone stimu-
lates lactation and increases concentrations of
calcium in serum (17, 200). The bulk of the
evidence suggests that parathyroid hormone is
not involved in the parturient paresis syndrome
(121). Hypocalcemia induces secretion of para-
thyroid hormone, which in turn stimulates pro-
duction of 1,25,dihydroxyvitamin D3, a potent
calcium (and phosphorus) mobilizing hormone
(46). This has been a new major area of re-
search that likely will yield much valuable in-
formation on regulation of calcium and phos-
phorus metabolism in normal mammary gland.
Although exogenous insulin has been known
for many years to suppress lactation, paradoxi-
cally, relative insufficiency of this hormone also
decreases milk yield (122). When extra glucose
is given, then exogenous insulin stimulates
lactation (101). Serum insulin concentrations
are related negatively to milk production (99),
although insulin uptake from blood occurs (12)
and receptors are in mammary tissue (135).
Although insulin is essential for maintenance of
mammary cells of mice in vitro (61), a recent
report (49) suggests that prolactin, even in the
absence of insulin, is capable of stimulating
secretion of large amounts of casein in vitro.
Removal of ovaries has little affect on post-
partum mammary growth or on synthesis of
milk (192). However, exogenous estrogens in-
hibit milk secretion. Indeed, estrogens have
been used clinically to inhibit unwanted lacta-
tion (109). Although progesterone inhibits
onset of lactation, it does not affect lactation
during the postpartum period (87). This may be
associated with the fact that progesterone has a
greater affinity for milk fat than for glucocorti-
coid receptors. Thus, milk fat may sequester
progesterone and thereby nullify its biological
activity. Alternatively, progesterone receptors
may disappear during lactation (81). Without
receptors, biological action of progesterone
would not occur.
Many of the hormones discussed are secreted
into milk (57, 118, 194). Progesterone concen-
trations in milk paralleled their concentrations
in blood. This has been used to practical advan-
tage to diagnose pregnancy in cattle (21).
Milk Ejection
The basic mechanism of the milk ejection
reflex was described by Ely and Peterson in
 PHYSIOLOGICAL CONTROL - 75TH ANNIVERSARY ISSUE
1941 (54). During the last quarter century the
neural pathway of this reflex was traced from
mammary gland to brain (42). It was estab-
lished that supraoptic and paraventricular
nuclei in the hypothalamus synthesized oxyto-
cin (206). In addition, oxytocin binds specifi-
cally to a protein, neurophysin I, to form
granules (92). The granules are transported
from their site of synthesis in neurons of the
supraoptic and paraventricular nuclei to their
site of storage in the posterior pituitary. Al-
though there are several reports of measure-
ments of oxytocin in blood, progress has been
relatively slow because of lack of a suitable assay.
Several radioimmunoassays for oxytocin that
required extraction of blood plasma were de-
veloped (15, 29, 30), and recently Gorewit
(67) developed a radioimmunoassay for oxyto-
cin in unextracted sera of cattle that appears to
be useful for studies of oxytocin release.
Oxytocin binding to receptors in mammary tis-
sue has been observed (169), but elucidation of
factors that regulate oxytocin release in blood
and binding to myoepithelial cells has just
begun to be investigated.
Ely and Petersen (54) reported in 1942 that
stressful stimuli inhibited milk ejection. In
intervening years much additional understand-
ing of this phenomenon has been gained (28).
For example, some stressful stimuli induce re-
lease of epinephrine and norepinephrine, which
cause vasoconstriction and reduce the amount
of oxytocin reaching the myoepithelial cells.
Moreover, epinephrine blocks oxytocin binding
to myoepithelial cells. Exogenous oxytocin
does not overcome this peripheral inhibition of
milk ejection. The most common cause of fail-
ure of the milk ejection reflex is associated with
stress of milking in early postpartum. This
stress sometimes inhibits release of oxytocin
from the posterior pituitary gland (44). Primi-
parous heifers, in early postpartum frequently
exhibit symptoms of central inhibition of milk
ejection. In these situations exogenous oxyto-
cin causes milk ejection. In afflicted heifers, it
is recommended that oxytocin be injected and
heifers milked because failure to remove milk,
especially in early lactation, may reduce milk
yield for duration of that lactation (203).
Other Physiological Factors
Affecting Lactation
There is no conclusive evidence that the
1413
efferent nervous system directly affects mam-
mary function. In fact, alveolar epithelial cells
of mammary gland do not receive innervation
(85). Indeed, in 1963 Linzell (113) showed that
complete denervation and transplantation of
the mammary gland to the neck of a goat did
not reduce milk yield provided the blood sup-
ply was reestablished. However, the nervous
system has major indirect effects on mammary
function. For example, milking initiates a
neural reflex that causes release of prolactin,
thyrotropin, adrenocorticotropin, and oxyto-
cin. These hormones in turn either directly
affect the mammary gland or do so through
respective target endocrine glands (189).
Secretion rates of milk are greatest and rela-
tively constant for 8 to 10 h after milking and
lowest just before milking (156, 193). In the
interval between milkings, intramammary pres-
sure and accumulated milk within the alveolar
lumen increase and inhibit high milk yields
(193). Indeed, omission of milkings in early
lactation in cows reduces milk production for
the entire lactation (203). Contrarily, increasing
milking frequency from twice to three times
daily increases milk production 10 to 25%,
and milking four times per day increases yield
another 5 to 15%. Greater frequencies of milk-
ing probably will become more common with
the advent of more automation in the milking
process. This will have the added advantage of
more frequent stimulation of release of several
galactopoietic hormones as previously de-
scribed.
Ovarian function has been associated with
milk production. For example, dairymen fre-
quently complain that milk yield is reduced
during estrus, and cows with ovarian follicular
cysts produce more milk than normal cows. In
1966 Johnson et al. (95) showed that cows pro-
duced more milk only after the cystic condition
developed. Thus, events associated with cystic
ovaries cause increased milk yield rather than
increased milk production causing follicular
cysts.
Blood flow is another physiological factor
that markedly affects production of milk.
Before 1956 it was established that the ratio of
blood flow to milk yield was approximately
500:1. Subsequent studies measured mammary
blood flow and cardiac output in conscious
lactating animals (74, 112). Mammary blood
flow is related linearly to milk secretion (149).
Journal of Dairy Science Vol. 64, No. 6, 1981
1414 TUCKER
The equation Y = 1.0 + .42 X, where Y = blood
flow in ml/min and X = milk yield in kg/day,
closely describes mammary blood flow in lacta-
ting cows (102). Mammary blood flow begins
to increase 2 to 3 days before parturition and
coincides with decreased uterine blood flow
associated with parturition (150). As milk
yield increases during early lactation, cardiac
output and blood flow to mammary gland, gut,
and liver markedly increase (76). As lactation
continues cardiac output becomes steady, but
there is an increased proportion of blood
directed toward mammary gland, gut, and liver
(76). Blood flow is associated closely with suck-
ling intensity and may be a mechanism whereby
milk yields are adjusted rapidly to demands of
the young. In addition, there is some evidence
that prolactin and growth hormone may in-
crease cardiac output of lactating animals
(75). Although there is evidence to the con-
trary in cows (119, 140), Hanwell and Linzell
(77) determined that accumulation of milk in
the mammary gland of the rat does not reduce
mammary blood flow; however, maintenance of
milk secretion and blood flow depends upon
intense suckling stimuli.
UNSOLVED PROBLEMS
FOR FUTURE RESEARCH
Although an abundance of information has
been published on physiological control of
mammary gland, we barely have begun to
understand how the mammary gland functions.
Thus, it seems prudent to predict that addi-
tional studies will be directed toward this end.
How this will be accomplished is much more
hazardous to predict. Nonetheless, investigators
in the future probably will direct their atten-
tion to at least some of the following problems.
Molecular Biology
Recently, molecular studies of biology have
erupted onto the research scene. Based on
studies of microbes, it is now theoretically pos-
sible to produce a variety of peptides and pro-
teins in practically unlimited quantities. Thus,
for the first time physiologists will have large
quantities of peptide hormones available to
answer definitively which hormones stimulate
mammary development, lactogenesis, and main-
tenance of lactation in large domestic animals.
Shortly after this information is available, such
Journal of Dairy Science Vol. 64, No. 6, 1981
compounds should become commercially avail-
able. A problem likely to be encountered is a
system to deliver proteins and peptides to dairy
animals. Perhaps researchers in dairy science
should begin now to consider development of
methods to administer proteins and peptides.
Of all the peptides known to affect mam-
mary function, growth hormone is one that
might be most promising commercially, because
it already is known that growth hormone stim-
ulates milk yield as well as b o d y growth in
cattle. It may be anticipated that the precise
role of prolactin in regulation of milk yields of
ruminants may become more clearly defined.
Hormone Receptors
Much has been learned about receptors for
hormones in a variety of tissues in laboratory
species, but relatively little has been done on
hormone receptors associated with lactation,
especially in domestic farm animal species.
Numbers of receptor sites can be manipulated,
but we know practically nothing about the
possibility of managing or selecting animals on
receptor sites to increase efficiency or pro-
duction of milk. Theoretically, manipulation of
amplification steps subsequent to binding is
another possibility whereby milk production
may be controlled. Before these possibilities
can be tested adequately, however, substantial
increases in information of these biochemical
processes must be gained.
Harvesting of Milk
Methods of harvesting milk have not
changed much since Ely and Petersen's classi-
cal research published in 1941. Scarcely an-
other area of dairy science has been so stagnant.
There is a major deficiency in our knowledge of
factors that control oxytocin synthesis, storage,
and release. In addition, at a normal milking 15
to 25% of milk is not removed at that milking,
but there are no practical methods available to
reduce this complementary milk. This area
needs much additional research.
Endocrine-Nutrient Metabolism
Hormones and nutrients interact to affect
secretion of milk, but research activity in this
area is woefully inadequate. Many of the tools
of research needed to study nutrient metabo-
lism and endocrinology are available. In fact,
 PHYSIOLOGICAL CONTROL - 75TH ANNIVERSARY ISSUE
this area m a y p r o v i d e a n early p a y o f f in de-
velopment of management schemes to enhance
p r o d u c t i v e e f f i c i e n c y o f dairy animals.
Genetic Basis of
Hormonal Control of Lactation
F e w studies o f h e r i t a b i l i t y of h o r m o n e s have
b e e n p u b l i s h e d , y e t t h e r e is p o t e n t i a l for selec-
t i o n o f a n i m a l s b a s e d o n t h e s e traits, especially
if it c o u l d b e a c c o m p l i s h e d at a n early age.
Because c o n c e n t r a t i o n s o f m a n y h o r m o n e s in
b l o o d vary m a r k e d l y f r o m t i m e t o t i m e , h o w -
ever, it is d i f f i c u l t t o k n o w w h e n t o m e a s u r e
h o r m o n e c o n c e n t r a t i o n . If m e a s u r e m e n t condi-
t i o n s are n o t s t a n d a r d i z e d , genetic c o n t r i b u -
t i o n s likely will be m a s k e d . F a c t o r s s u c h as
clearance rates a n d s e c r e t i o n rates o f h o r m o n e s
also m a y have t o b e c o n s i d e r e d . Perhaps h e r i t a -
bility of h o r m o n e s in m i l k s h o u l d b e m e a s u r e d .
A l t h o u g h t h e genetic basis o f h o r m o n e secre-
t i o n is a n i m p o r t a n t area, progress is likely t o
b e slow, if for n o o t h e r r e a s o n t h a n p h y s i o l o -
gists a n d geneticists t o d a t e have n o t m a d e g r e a t
progress in learning a n d a p p l y i n g t e c h n i q u e s o f
t h e o t h e r ' s discipline.
Environmental Impacts
on Mammary Function
Studies o f q u a n t i t a t i v e effects of t e m p e r a -
t u r e , light, h u m i d i t y , w i n d v e l o c i t y , a n d o t h e r
c l i m a t i c variables o n h o r m o n e s a n d m a m m a r y
f u n c t i o n p r o b a b l y will receive increased s t u d y
in t h e f u t u r e . Diurnal a n d circadian r h y t h m s in
h o r m o n e s e c r e t i o n , n u t r i e n t m e t a b o l i s m , feed-
ing p a t t e r n s , a n d m a m m a r y tissue m e t a b o l i s m
n e e d to be d e t e r m i n e d . It is likely t h a t t h e s e
studies will lead to n e w m e t h o d s o f increasing
efficiency of milk production.
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 PHYSIOLOGICAL CONTROL - 75TH ANNIVERSARY ISSUE
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Journal of Dairy Science Vol. 64, No. 6, 1981