Hormonal Control of Mammogenesis and Onset of

Lactation in C o w s - A Review ~

R. E. ERB
Department of Animal Sciences
Purdue University
West Lafayette, IN 47907

ABSTRACT INTRODUCTION
Estrogen stimulates development of Biology of lactation has been studied for
mammary ducts, and progesterone and several centuries. The first documented reviews
estrogen stimulate proliferation of secre- were in 1765 and 1778 by VonHaller (23).
tory tissues. In vivo, sequential addition Subsequent reviews (Rothchild, 1901 to 1902;
of insulin (step 1), glucocorticoid (step Simon, 1968) included over 11,000 references
2), and prolactin (step 3) leads to biosyn- for 1700 to 1928, as cited by Cowie and Tindal
thesis of casein and lactose. In cows, (23). Since 1928 an extraordinary number of
mammogenesis continues until termina- reviews and books have been published which
tion of pregnancy and overlaps onset of include discussions on endocrinology of lacta-
lactation. Progesterone probably inhibits tion. Reviews cited in the text are (4, 19, 21,
differentiation of secretory cells at step 2 23, 26, 27, 29, 47, 64, 65, 68, 80, 82, 101,
or step 3. Sensitivity of individual cells to 102, 103, 109, 110, 113).
progestational inhibition may decrease The primary purpose of this paper is to
variably which may be interdependent review hormonal control of mammogenesis
upon relative increases in estrogen, pro- (growth and differentiation to stage prior to
lactin, corticoids, and growth hormone to active secretion) and onset of lactation (start of
cause asynchronies among them at calv- active secretion) in dairy cows. Research on
ing. Since prolactin in plasma is not other species (mainly goats, mice, rabbits, rats,
correlated with progesterone or the estro- and sheep) will be cited as necessary to support
gens, factors other than feed-back effects hypotheses regarding hormonal effects on lacta-
of ovarian steroids may be responsible for tion cycles.
its sustained increase periparturiently. Al-
so, elevated prolactin periparturiently
may be unrelated to subsequent rates of HISTORICAL
lactation because its "basal" concentra- Artificial development of udder function,
tions may meet requirements when in- equivalent to that expected following preg-
hibiting effects of progesterone are re- nancy and parturition, has been attempted with
moved. This concept is attractive because increasing frequency since 1897. It was demon-
mammary ceils neither are synchronized strated initially that reintroduction of ovarian
highly for biosynthesis nor secrete normal tissue into ovariectomized animals permitted
milk for several days after calving. At the continued growth of mammary glands (42, 61).
latter time, concentrations in plasma are Hormonal stimulation was postulated in 1906
low for progesterone and estrogen, similar (63). Later (1909 to 1914), mammary growth
to 3 days before calving for glucocorti- was associated with successive estrous periods
coids and prolactin, and increasing for and with development of corpora lutea (eL)
insulin. Evidence of lactation under un- following sterile copulation (23). This led to
usual circumstances was discussed. conclusion that mammary growth was caused
by CL (corpus luteum) of pregnancy (3, 44).
The pituitary was implicated 14 yr later by
showing, in rabbits, that crude extracts of
Received July 1, 1976. pituitary initiated lactation in developed mam-
~Journal Paper No. 6316, Purdue University Agri-
cultural Experiment Station. Text of invitational mary glands (97), and also caused mammary
paper presented during 71st Annual Meeting, Ameri- proliferation in undeveloped glands (78). Then
can Dairy Scierice Association. in castrate male rabbits "estrus producing hor-

155
156 ERB

mone" (estrogen) in extracts of urine from Continued efforts to initiate lactation by

pregnant cows stimulated only mammary duct treatment and nonpregnant heifers or dry cows
development. Moreover, mixtures of estrogen with various combinations of estrogen and
and progesterone stimulated mammary prolifer- progesterone for 7 to 180 days has not resulted
ation equivalent to late pregnancy in female in average milk production equal to amounts
rabbits, but progesterone alone was without expected after parturition (17, 34, 45, 49, 65,
effect (111, 112). 72, 90, 91, 92, 110, 114, 115, 117, 118, 119).
By 1931, it was understood in a general way Because of long treatment times, commercial
that both mammary proliferation and lactation applications for hormonal induction of lacta-
were stimulated by ovarian and pituitary hor- tion were considered impractical prior to 1973.
mones (80, 109, 113). It was recognized that However, a 7-day treatment, used subsequently
maximal lactation response was associated with by Smith and Schanbacher (91), could have
a variety of hormonal changes characteristic of practical application for salvage of cows non-
pregnancy and parturition, which included a) pregnant at end of normal lactations because
prolonged secretion of CL hormones, b) in- fertility seems normal after treatment. How-
creases in estrogen during late pregnancy, and ever, average milk yields after 7-day treatments
c) appropriate but undefined pituitary and do not appear superior to those resulting from
placental hormones. long treatments. Successful induction rates of
Prior to 1928, substantial development of about 70% and lactation yields 65 to 70% as
mammary glands and variable amounts of secre- high as prior years among cows lactating after
tion were produced by implants of tissue (7) or treatment (34, 47, 90, 91), seem remarkable for
injection of extracts of various reproductive only 7 days of hormonal treatment (47).
tissues (7, 36, 38, 63). Steinach et al. (96) However, the cows ordinarily do not initiate
apparently were first to report full milk secre- lactation until 3 to 4 wk after first treatment,
tion in castrated animals (male and female and rate of increase in daily yields are subnor-
guinea pigs) after daily injections of purified mal (33). Since dry periods of 6 to 8 wk are
"estrus producing hormone" for 7 to 8 wk. recommended prior to calving and about 3 wk
Evans (35) obtained milk from three virgin are required after last milking before biochemi-
goats, one dry goat, and a heifer by injecting cal stasis can be observed" in the udder (85,
extracts from the anterior pituitary. However, 116), some cows may have only 3 to 5 wk to
the technique was not successful when tried by regenerate secretory tissues before calving. The
others (5, 11). Later, udders of virgin goats preceding analogy suggests that full lactation in
were developed by inunction with estradiol induced cows should not be limited because of
benzoate, and lactation was initiated by inject- short periods for treatment, and that it may be
ing pituitary "lactogenic" hormone (25). possible to discover correct application of
Artificial induction of lactation was at- hormones to induce regularly full lactation.
tempted with other synthetic estrogens (inunc-
Q U A L I T A T I V E HORMONAL
tion of udder, implants, injections, and oral
REQUI REMENTS
administration) from about 1939 to 1946.
Results of these experiments have been sum- Development and differentiation of parent
marized by Meites (65). Diethylstilbestrol cells in mammary tissue from mice at mid-preg-
(DES) was used most extensively, although nancy, incubated as organ cultures, proceeded
other synthetic estrogenic compounds were in a time-dependent, hormone-dependent se-
investigated, including hexestrol and various quence (82, 101, 102 for review). The required
esters of hexestrol and DES. Lactation re- sequence was a) insulin which induced only one
sponses induced by treatments with synthetic division of parent cells, b) hydrocortisone for
estrogens were variable and difficuh to repro- differentiation of the daughter cells, c) prolac-
duce. Finally, there was general agreement that tin to initiate active synthesis and secretion.
estrogen alone failed to develop normal mam- Each sequence required about 2 days for
mary secretory tissue of cows and goats and maximum response (102). If sequential devel-
that this defect could be corrected by extended opment was interrupted for as long as 4 days by
treatment (30 to 180 days) with estrogen and nonaddition of either hydrocortisone or prolac-
progesterone (8, 71,100). tin, daughter cells regressed to the cytological

Journal of Dairy Science Vol. 60, No. 2

 REVIEW: HORMONES FOR MAMMOGENESISAND LACTATION 157

appearance of parent cells. The same sequential centrations in plasma and mammary secretions
changes occurred when embryonic (12, 13) or may increase before progesterone decreases to
prepubertal (120) mammary tissues were incu- low concentrations. Whatever the mechanisms
bated under similar conditions. Cultured mam- in cows, cytologically (4, 7, 82) and otherwise
mary explants from nonlactating cows 40 days (26, 82), the effect is not simultaneous for all
prepartum required insulin for survival, hydro- cells perhaps due to differences in circulation to
cortisone for differentiation, and prolactin for their sites. Because estrogen continues to in-
biosynthesis (16). Requirements appeared simi- crease until parturition, it may stimulate pitui-
lar when mammary explants were from heifers tary release of prolactin (65, 66, 67, 83) and
pretreated with estrogen and progesterone al- enhance rate of milk secretion or perhaps
though addition of estrogen and progesterone synergize mechanisms required for onset of
or calf plasma further improved indicators of normal lactation, such as function of corticoids
lactogenesis (76). (103), growth hormone (21), prolactin (21,
Based on in vitro results, parent cells should 84), placental lactogen (9), and other factors in
advance to active secretion in vivo from a blood plasma (76). However, estrogen decreases
variety of normal or abnormal conditions. Since to low concentrations within 72 h after calving
parent cells are at all stages after the embry- (19, 31). Therefore, lactation does not ap-
onic mammary primary sprout stage, this con- proach maximum rates until after plasma and
cept helps explain what appears to be diverse urinary estrogen are low. Moreover, basal con-
observations regarding onset of lactation. Lacta- centrations of prolactin in blood are decreased
tion may occur spontaneously in virgin goats within 2 days after calving (55, 56) although
(37), in suckled virgin heifers (108), in heifers episodic release occurs thereafter from diverse
milked as early as 120 days of first pregnancy stimuli including milking (19, 62). Also oxy-
(5, 108) or following abortion (99), and follow- tocin release and regular removal of milk are
ing hormone treatments prepartum (105), dur- essential for increase to maximum rates and for
ing lactation (72), or during dry periods of sustained lactation (82).
nonpregnant cows (17, 18, 23a, 34, 45, 65, 75,
90, 91).
The udders of heifers develop throughout Q U A N T I T A T I V E C H A N G E S IN
HORMONES
pregnancy. However, differentiation, synthesis
capability, and active synthesis, are relatively Progesterone in blood decreases rapidly 2 to
incomplete in cattle until about 2 days before 3 days before calving (19, 30, 54, 95) whereas
parturition (4, 47, 59, 82) unless altered by prolactin (19, 30, 50, 55, 5 6 ) a n d growth
prepartum milking (1). Since mammary tissue is hormone (19, 55) increase 1 to 2 days before
exposed constantly to the metabolic hormones calving and remain elevated for 1 to 2 more
and, at least to low concentrations of prolactin days. Growth hormone decreases and insulin
in vivo, changing concentrations of progester- increases during the 1st mo after calving (93).
one and estrogen in blood must be involved Glucocorticoids increase significantly in blood
until onset of lactation. This role includes a) serum only during calving and decrease to
mammary duct development by estrogen, b) precalving concentrations within 12 h after
lobule-alveolar development through synergistic calving (19, 30, 53, 95). The parturient increase
effects of estrogen and progesterone, and c) in glucocorticoids may be due to stress of
nearly complete synchronization of secretory parturition (20, 53), which suggests that the
cells ready for differentiation prior to secretion increase per se may have little significance
(4, 82). It is unknown if roles of estrogen and regarding onset of lactation. Estrogens in blood
progesterone are primary or secondary, but plasma (15, 28, 81) or serum (19, 95), urine
onset of lactation is associated with their rapid (54), and mammary secretion (15, 73) increase
changes in concentration periparturiently. rapidly during the last 1 wk of pregnancy.
Progesterone appears the most probable in- Concentrations in blood are near maximum the
hibitor of onset of lactation (23, 46, 106). day before calving and in urine (31, 54) or milk
Until the progesterone block is removed, pro- (31) during the 1st day after calving.
lactin may be unable to initiate synthesis of Data are more limited regarding periparturi-
~-lactalbumin and lactose even though its con- ent changes in the 17/3 and 17& isomers of

Journal of Dairy Science Vol. 60, No. 2

158 ERB

estradiol. Although circulating estrone predomi- Average changes prepartum in plasma for
nates, it seems clear that both isomers of progesterone and the estrogens are suggestive of
estradiol also increase during late gestation (15, a temporal relationship with prolactin (Table
28, 81). Variations of up to 10-fold in amounts 1). However, prolactin was not correlated with
of each estrogen in blood, urine, and mammary progesterone or the estrogens in the same
secretions are not uncommon among cows on samples of plasma, either 3 to 6 days before
the same day before calving. Biological signifi- calving or 2 days before to .5 day after calving.
cance of such large variations is not understood, Moreover, percent lactose in secretions was not
especially as these may influence traits of correlated with concentrations of the aforemen-
parturition, synchronies of biosynthesis and tioned hormones in plasma. This suggests that
secretion, and subsequent rates of milk yield. concentrations in plasma of other hormones
Hormonal profiles at or near calving support [insulin (16, 76, 89), corticoids (16, 76, 89,
a hypothesis that progesterone inhibits either 95), growth hormones (55), placental lactogen
the release or biological activity of pituitary (9), or other constituents in plasma (76)1 may
prolactin. In addition, either low ratios of be related more directly to morphological
progesterone to estrogen or increased estrogen changes prior to onset of normal lactation.
alone triggers parturition and may enhance Since differentiation, indicators of biosynthesis,
release of prolactin from the pituitary (83, 88). and rates of biosynthesis appear to occur
We have completed a study with 22 cows step-wise over several days in organ culture
and heifers. Blood and mammary secretions (101, 102), correlations between prolactin and
were collected daily from 6.8 + .3 days before lactose and other peripheral hormones on the
calving to 2 days after calving (15). Concentra- same day may not reveal the true significance
tions of immunoreactive prolactin, progester- of the temporal changes.
one, estrone, estradiol-17/3, and residual estradi- Peripheral concentrations of hormones in
ol (believed to be primarily 17-~) were mea- vivo may be inappropriate to define their
sured to evaluate their relationships to onset of effects on mammary secretory cells or other
normal lactation. Concentrations of lactose in target activities for several reasons. Average
mammary secretions were measured to evaluate concentrations are predicted from samples usu-
synchrony of synthesis among secretory cells ally collected in less than 1 rain at infrequent
(29, 82,102). intervals of hours to several days. Even if
Average concentrations of the hormones in "basal" concentrations are estimated reason-
plasma for periparturient intervals in Table 1 ably well, these may be well above concentra-
are typical of other data (19, 28, 95, 103). tion gradients required to initiate or maintain a
Concentrations in mammary secretions (re- specific biological action. Since biological ac-
ferred to as milk hereafter) mimicked changes tivity seems dependent on hormone-receptor
in plasma, but there were differences in ratios interaction at the cellular level (27), the degree
among concentrations of hormones in milk of receptor saturation should be of greatest
compared to plasma (31). Prolactin, progester- importance. Periparturiently, mammary tissue
one, and estradiol-17/3 were higher (P<.01) in may be capable of concentrating certain hor-
milk than in blood plasma whereas estrone was mones such as estradiol-17~ and progesterone
lower (P<.01) in milk, and estradiol-17~ con- (Table 1) either dissolved in lipids or bound to
centrations were not different (Table 1) (31). various high and low affinity binding sites.
Shifts in ratios of hormonal concentrations in For example, preparations from cow mam-
plasma and milk from 3 to 6 days prepartum to mary tissue contain a heat resistant component
day of calving (partum +- .5 day; Table 1) which has low affinity hut large capacity for
suggest relative changes in hormonal transport. binding cortisol (104). However, there is no
Average ratios (milk:plasma) prepartum for evidence that this binding "protein" is specific
prolactin decreased progressively, whereas those for cortisol. The same preparation had high
for progesterone and the estradiols increased. affinity receptors which competed strongly for
Estrone ratios were unchanged. None of these progesterone and the corticoids (6, 104). Prepa-
hormones was correlated significantly with per- rations from breast tumor tissue show evidence
cent fat in the prepartum mammary secretions of receptors specific for progesterone (52).
(r = .15 to --.14). High affinity receptors specific for cortisol (41,

Journal of Dairy Science Vol. 60, No. 2

 T A B L E 1. Comparison o f h o r m o n e s in blood plasma and m a m m a r y secretions at intervals before, day of, and after parturition. Data s u m m a r i z e d from Chew et al.
(15).

Prepartum Postpartum
Comparison 3 to 6 days 1 to 2 days Partum -+ .5 days 1 to 2 days

Blood plasma (n) 59 41 42 44 :n

Prolactin (ng/ml) 28.8 ± 2.1 a 57.7 ± 7.0 73.5 ± 4.6 25.5 ± 2.5 o
Progesterone (ng/ml) 3.6 .2 2.8 .2 1.3 .1 .7 .02
Estradiol-17/3 (pg/ml) 276 23 423 41 388 40 74 14 o
Estradiol-17~ (pg/ml) 970 106 927 134 944 126 313 41 z
Estrone (pg/ml) 3146 307 3513 345 2095 347 373 89 r~

0
M a m m a r y secretions (n) 46 33 43 44
Prolactin (ng/ml) 148 13 201 26 212 18 83 8
Progesterone (ng/ml) 4.8 .5 5.1 •5 4.0 .4 1.4 .2
Estradiol-17~ (pg/ml) 509 64 509 39 609 74 124 14
Estradiol-17c~ (pg/ml) 630 90 620 86 1175 164 419 57
Estrone (pg/ml) 1719 192 1952 215 1620 210 288 67
Lactose (%) 2.6 .2 3.2 .2 3.2 .1 3.9 .1 Z
Fat (%) 3.3 .4 4.1 .6 5.3 .4 4.5 .4
r~
Total protein (%) 7.7 .4 6.9 .4 7.5 .4 5.6 .2

e- M a m m a r y secretions/plasma
(ratio)
Prolactin 5.1 3.5 2.9 3.2
Progesterone 1.3 1.8 3.1 2.0
Estradiol-17~3 1.8 1.2 1.6 1.7
Estradiol-17a .6 .7 1.2 1.3 0
Z
Estrone .5 .6 .6 .8

< aAverage ± standard error.

o

o
~o xO
160 ERB

87) have been found in udder tissue from tions (15, 31) during late pregnancy as com-
lactating cows (41). Receptors for progesterone pared to estrone and estradiol-t7a. Moreover,
and corticoids may have special significance temporal changes in concentrations of the
because corticoids stimulate proliferation of major estrogens appear proportional in mam-
rough endoplasmic reticulum while progester- mary secretions or plasma periparturiendy (Ta-
one is inhibitory (82, 103 for review). There- ble 1).
fore, if concentrations of progesterone de- Selective uptake from plasma (14, 48) and
creased or corticoids increased, this should shift metabolism (89) of progesterone by mammary
ratios of "occupied" high affinity receptor tissue have been reported. Therefore, uptake,
sites. Also, mammary tissue may metabolize storage, compartmentation within the ceils,
certain steroids (89), and metabolism may metabolism, and mechanism of action of estro-
occur at different rates for specific hormones. gens in mammary tissue seem worthy of study.
If, for example, progesterone was metabolized Does the mammary gland differentially concen-
more efficiently than corticoids, then differ- trate the estrogens? Differences in ratios of
ences in rate of degradation, and possibly their concentrations in mammary secretions
disproportionate changes in blood flow among compared to plasma suggest differences in
local areas of the udder due to increasing mammary transport, especially between estrone
congestion, could account for variations among and the estradiols (Table 1). Also, to what
alveoli in regard to whether or not their extent does mammary tissue convert estrone to
secretory cells were cytologically mature or the estradiols? Conversion of estrone to estradi-
juvenile prior to calving (82). A similar mecha- o1-17~3 may occur as indicated by a three-fold
nism may be operative, even when plasma average difference in their mammary secre-
progesterone is relatively high, if basal concen- tion/plasma ratios (Table 1). Changes in the
trations of corticoids also are elevated. This ratios for estradiol-17c~ from prepartum to
could explain variable rates of secretion among postpartum (Table 1), indicate either more
cows milked prepartum. Finally, the above efficient removal of estradiol-17a or increased
hypothesis could explain why lactation was formation from estrone and estradiol-17/L Such
initiated with a synthetic corticoid in preg- conversions, if they occur at all in mammary
nant heifers (105), or why rapid mammary tissue, should occur throughout the gland,
build-up and lactation seem to occur when including secretions stored in alveolar lumina.
births are induced prematurely with dexa- This is postulated because enzymes appropriate
methasone (86). The latter synthetic gluco- for such conversion apparently are in blood and
corticoid competes with cortisol in preparations elsewhere (70 for review). Therefore, such
containing the mammary corticoid receptor enzymes may be in mammary secretions. Con-
(41,104). version of estrone to estradiol-17/3 near sites of
Interrelationships with other high affinity action may have a marked effect on their
receptors may be equally or more impor- relative concentration gradients in fluids in
tant. These include receptors for insulin (77) contact with cell surface membranes. An alter-
and prolactin (39) in plasma membrane of native would be selective uptake, in or on the
secretory ceils, and for estrogens in cyto- plasma membrane, by mechanisms which favor
plasmic fractions and nuclear pellets (40). a specific estrogen. Since mammary cell recep-
Growth homaone and chorionic somato- tors for estrogen are in cytosol and nuclear
mammotropin appear to compete with pro- isolates, a two-step mechanism of action has
lactin for the same receptor (39), and possi- been postulated (40). Therefore, cellular entry
bly placental lactogen as well. of at least the biologically active estrogen(s)
Cytosol receptors for estrogen appear specif- would be essential. Certain estrogens probably
ic and compete equally for estrone, estradiol- enter mammary cells at all stages of function,
17/3, and estriol (40). The significance of equal because of stimulatory effects on mammogene-
competitive binding among estrogens is not sis, and other effects which vary from stimula-
understood. Although estradiol-17~3 appears to tion of lactation to udder regression as dosages
be the biologically active endogenous estrogen, are increased (65, 72 for review). Moreover,
its concentrations are relatively low in bovine immunoreactive estrogens are in milk (31, 34,
plasma (15, 28, 31, 81) and mammary secre- 72, 73).

Journal of Dairy Science Vol. 60, No. 2

 REVIEW: HORMONES FOR MAMMOGENESISAND LACTATION 161

EFFECT OF E X O G E N O U S H O R M O N E S different rates, and onset of lactation and

maximum rates of milk production were vari-
Mammogenesis and Induction of Lactation able (34, 58, 117).

Even though lactations induced exogenously

Lactational Performance and
are nearly always inferior to those induced by Hormone Concentrations
pregnancy, it seems worthwhile to review what
has been learned from experiments with domes- We recently compared concentrations of
tic ruminants. Milk production at subnormal progesterone, estrogen, and prolactin in blood
rates can be induced inconsistently in nonpreg- plasma with lactations traits induced in 29 cows
nant, dry cows, goats (65 for review), and ewes by treatment with E2/3 and P for 7 days (33).
(79) by chronic treatment with various estro- Superior, median, and inferior lactations were
gens. Mammary morphology is generally abnor- identified by ranking both weight-age adjusted
mal (65 for review). Brief pretreatment with milk yields for 7 consecutive days at peak
estrogen, prolonged treatment (30 to 180 day) lactation and days for milk yield to increase
with a mixture of progesterone and estrogen from 5 to 10 kg/day. Plasma hormones were
(ratios of at least 1000:1), and continuation of measured on day 0 before first treatment (day
estrogen after withdrawal of progesterone in- 1), and on days 7, 14, 17, 21, 24, 28, and 35.
duced lactation consistently (65, 115, 118). Cows having superior lactations a) had below
Subsequent milk yields were equivalent in some average progesterone and estrogen before treat-
cows to yields expected after calving (65, 110, ment (day 0), b) decreased rapidly in progester-
115, 118). one and estrogen after treatment ended and
Although no direct comparisons have been remained low thereafter, and c) had increased
made, it appears that mammogenesis and subse- prolactin in plasma from day 14 to 35. Al-
quent rates of lactation are more variable though prolactin also was elevated in the
following treatment for 7 days with progester- median group, estrogen and progesterone were
one (P) and estradiol-17/3 (E2/3) at a ratio of higher for days 21 to 35 as compared with the
2.5:1 (.25 mg and .1 mg/kg/day) than for long superior group. In comparison to superior and
treatments. Limited evidence suggests that median groups, the inferior group had above
synchrony among secretory cells at onset of average estrogen at end of treatment (day 7)
lactation after 7-day treatment is substantially which decreased more rapidly between days 7
less than for mammary tissue at calving (18, and 14. Also, plasma prolactin was chronically
23a, 47, 75). Also, failures, or otherwise re- lower from days 21 to 35. On day 0 plasma
duced lactation yields, occurred most frequent- concentrations of progesterone as well as pro-
ly among cows in mid to late luteal phase when lactin were significantly correlated (positive)
7-day treatment was initiated (90). The forego- with their concentrations on certain subsequent
ing observations suggest that mammary cells days (14 to 35 for progesterone and days 7, 21,
may be refractory unless there is prior priming 28, and 35 for prolactin). In contrast, day 0
with estrogen as would be the case just prior to plasma estrogen was correlated only with its
estrus. Amounts of estrogen required for prim- day-7 concentrations. Concentrations of plasma
ing may be low when progesterone is low, as in estrogen as well as plasma progesterone consis-
ovariectomized cows, or high when progester- tently were correlated (r = .33 to .92) among
one is high. Circulating estrogen is characteris- subsequent days starting with day 17. Plasma
tically low between days 10 and 17 of the prolactin was correlated significantly with plas-
estrous cycle (32, 103). Average total estrogen ma estrogen in the same sample only on day 21
and progesterone in plasma at end of 7-day (r = .52), and not correlated with progesterone
treatment with E2~3 and P approximate concen- at any time. Failure to observe significant
trations observed during the last 3 to 7 days of correlations between plasma prolactin and ovar-
pregnancy (15, 31, 95, 103). However, varia- ian steroids, except with estrogen on day 21, is
tions were large among individuals not only consistent with similar comparisons in peripart-
during treatment but for several weeks after urient cows (see preceding section). From our
treatment (33, 34). Moreover, among cows studies of temporal changes in plasma hor-
depletion of plasma hormones occurred at mones prior to, during, and after onset of

Journal of Dairy Science Vol. 60, No. 2

162 ERa

lactation induced with E23 and P, several facets (24). However, effects on milk yield were
are of interest: a) concentrations of progester- inconclusive. Inability to demonstrate superior
one pretreatment were correlated positively initiation of hormonally induced lactations by
with concentrations thereafter (33); b) pro- treatment with TRH may be due to several
longed elevation of progesterone (above .5 factors. Endogenous prolactin (24, 33, 34, 88,
ng/ml) after day 17 either inhibited lactation, 117) and growth hormone (24) were increased
and/or delayed onset of lactation (33, 117); before TRH was administered. Therefore, fur-
and c) occurrence of significant differences in ther increases may have had no effect on the
hormonal profiles associated with inferior lacta- average individual. Temporal increases in pro-
tions as compared to superior lactations (33). lactin and growth hormone could have been
The major differences associated with inferior ineffective because a majority of secretory cells
lactations were high titers of estrogen in plasma were not differentiated at time of treatment or
on last day of treatment (day 7) and failure to because concentrations were elevated only
maintain above average liters (290 to 900 briefly. Finally, timing of treatments with TRH
pg/ml) through days 14 and 17 concurrent with may have been incorrect.
rapid decreases in progesterone (33, 117). Also, Various attempts to evaluate the relative
the group with inferior lactations showed slow importance of prolactin for initiation and main-
decrease in total estrogen (33) or specifically tenance of lactation in intact ruminants have
total estradio[ (58) and had chronically low been inconclusive. However, its requirement for
average prolactin (less than 24 ng/ml) after day initiation of lactation has not been questioned
17 (33, 58). (19, 65 for review). Milk yield of a goat
decreased rapidly after hypophysectomy (21,
Requirements for Prolactin
22). Synthetic glucocorticoid was administered
after hypophysectomy. Additional treatment
Consistent increases in plasma prolactin peri- with growth hormone and triiodothyronine
parturiently (15, 31, 55, 56, 103) or after iT3) begun about 70 days after hypophysecto-
termination of treatment with E23 and P for 7 my resulted in about 30% restoration of milk
days (33, 34, 72, 117) suggest, but do not yield. When ovine prolactin also was included,
prove, its requirement for onset of lactation in about 25 days later, lactation was restored
cows. Depression of plasma prolactin with completely. After restoration, lactation was
ergocryptine appears to have little or no effect maintained without prolactin. Then hormonal
on established lactation (57, 94) and appears to requirements for maintenance of lactation in a
inhibit onset of lactation and subsequent milk hypophysectomized goat were synthetic gluco-
yield only ~if treatment is started prior to corticoid, growth hormone, T3, and presum-
calving and is continued until after calving (57, ably, endogenous insulin and glucagon. It is
84). Cessation of treatment prior to calving had intriguing that secretory structures apparently
less effect even though prolactin in plasma was remained intact for over 3 mo of minimal
reduced temporarily to low concentrations secretory activity before restoration. It seems
(84). unlikely that regression occurred and new
Synthetic thyrotropin releasing hormone secretory structures regenerated in the absence
(TRH) causes immediate but short term in- of estrogen and progesterone. Continued mam-
creases in thyroxine, prolactin and growth mary stimulation and removal of secretion may
hormone of plasma (20). However, response to explain partially the apparent maintenance of
TRH as an additional treatment for hormonally the goat's secretory tissues (21, 82).
induced lactation in cows (74) and ewes (24,
and unpublished data) does not appear promis-
ing. Lactational responses were similar for A CONCEPT OF HORMONAL
CONTROL-RUMINANTS
groups injected with saline or TRH 7 to 10 days
(cows; 74) or 10 to 13 days (ewes; unpub- There has been general agreement for many
lished) after last treatment with E23 and P. years that lactation cycles are controlled by
When TRH or saline was injected into estrogen- estrogen and progesterone (4, 98, 103, 109,
ized ewes 14 to 17 days after last E23 and P, 111). The changes in each are synchronized for
TRH caused faster increase in percent lactose mammary development, completion of preg-

Journal of Dairy Science Vol. 60, No. 2

 REVIEW: HORMONES FOR MAMMOGENESISAND LACTATION 163

nancy, and lactation. In heifers, allometric negative correlations periparturiently between

growth of the udder starts prior to puberty and progesterone and prolactin in blood plasma. It
plateaus between 9 and 12 mo of age (98). seems necessary at least in cows to consider
Estrogen alone stimulates duct proliferation, that lactation by all cells is not normal until
but normal lobule-alveolar development re- their secretions are characteristic of normal
quires synergistic effects of estrogen and pro- milk. The latter does not occur for several days
gesterone (4 for review). Moreover, since alveoli postpartum even when cows are milked pre-
are absent prior to first pregnancy (82 for partum (unpublished). Therefore, the prior
review), except under anomalous circum- variable indicators of onset of lactation, such as
stances, it is assumed that concentrations of cytological and biochemical indicators, and
estrogen and/or progesterone are either too low accumulation of secretions, only represent
or elevated too briefly during estrous cycles to stages associated with maturity of secretory
synergize lobule-alveolar development. Develop- function.
ment of mammary glands, capable of milk Ratios of progesterone to estrogen in plasma
production consistent with genotype of the decrease rapidly for 1 to 3 days before parturi-
individual, requires sustained high concentra- tion (103) (Table 1) and may be more impor-
tions of estrogen and progesterone followed by tant in triggering traits of parturition and onset
decreases in both periparturiently. Apparently, of lactation than their absolute concentrations
maximum time required for regression and at any specific time. Although concentrations
regeneration of mammary secretory ceils does in plasma of pituitary prolactin, growth hor-
not exceed 6 to 7 wk in dairy cows because mone, corticoids, insulin, and oxytocin increase
subsequent lactation yields are lowered only if periparturiently, such changes may be mediated
dry periods are less than 6 wk (60). Actual time by anxiety and discomfort prior to initiation of
for complete regeneration during late pregnan- parturition and to stress during parturition (19,
cy of dairy cows may be 3 wk or less unless 53). Our failure to find significant correlations
regression and regeneration occur simultaneous- periparturiently between concentrations of pi-
ly. tuitary prolactin and ovarian steroids in plasma
Progesterone is the primary inhibitor of and percent lactose in mammary secretions
parturition, and it seems appropriate to assign it during the same day suggests other mechanisms.
a similar role in onset of lactation. Based on However, the hormonal comparisons with per-
recent studies (1, 16, 76, 89, 101, 102), a cent lactose may not be realistic due to
concept should account for sequential develop- asynchronies among secretory cells prior to the
ment of secretory cells in vitro (step 1 - a t least end of parturition (82). In this case, any effects
one division of parent cells requiring insulin, on percent lactose in mammary secretions may
step 2-organelle formation in daughter cells not occur for several days (101, 102).
requiring cortisol, and step 3-secretory capa- Even though perip/arturient changes in other
bility requiring prolactin). Why should it not circulating hormones may be inhibited partially
postulate that progesterone inhibits step 2 via by progesterone or ;stimulated partially by one
the corticoid and progesterone receptors? Then or more of the estrogens, their average increase
it is relatively easy to visualize asynchronies may not be reflected by averaging gross mea-
among cells regarding their stage of differentia- surements of rates of synthesis and secretion. In
tion during late pregnancy (82). Incomplete other words, the possibility remains that "ba-
inhibition affecting rate of differentiation could sal" concentrations of other hormones meet
occur in certain treatments and certainly should requirements for onset of lactation once the
exist during terminal stages of pregnancy when postulated block of step 2 by progesterone is
concentrations of progesterone are decreasing removed. Under the latter concept the effect of
at different rates among cows. Also, degree of estrogen on mammary secretory ceils could be
inhibition of step 2 by progesterone could be simplified. Why should it not postulate positive
dependent on concentrations of glucocorticoids effects similar to its action on myometrial
and need not have a direct effect on release or tissues when not inhibited by progesterone?
action of prolactin. Even large amounts of Then direct effects of estrogen on mammary
prolactin may be ineffective until step 2 is tissues would be a) increased permeability of
completed which could explain absence of cellular membranes, b) accumulation of fluid in

Journal of Dairy Science Vol. 60, No. 2

164 ERB

extracellular spaces (congestion and edema), c) tions secretory cell proliferation may occur.
increased vascularity and, presumably, blood Such cells should differentiate either because of
flow rate, and d) stimulation of RNA-directed chronically low progesterone before puberty or
synthesis of cellular proteins (107). Copious when a corpus luteum regressed. Substantial
synthesis and secretion of casein, ~-lactalbumin, yields of milk by heifers manually stimulated
and lactose cannot be explained well if assigned during pregnancy or injected with synthetic
directly to effects of estrogen. This aspect may glucocorticoid (105), emphasizes potential for
be assigned more properly to catalyzing effects stimulating secretory structures prior to first
of insulin, corticoids, prolactin, growth hor- calving. The effect of exogenous glucocorticoid
mone, and oxytocin, along with the mandatory presumably would override inhibitory effects of
requirement that secretions be removed regular- progesterone and probably also inhibit luteal
ly postpartum. In fact, the conceptual role secretion rates as well since treated heifers
assigned to estrogen may not be necessary for calved 25 days early. It is also possible that
normal or near normal lactation once the manual stimulation and milking reduced luteal
progesterone block of step 2 is removed or is function since untreated controls calved 12
otherwise overcome by endogenous or exoge- days before expected due dates (105).
nous glucocorticoids via appropriate receptors. Prepartum milking also can be considered
At least two natural phenomena in cows can be anomalous. Low yields of secretion by some
cited as evidence. Cows with prolonged gesta- individuals milked only during terminal stages
tion characteristically have elevated progester- of pregnancy could be due to above-average
one and low estrogen (10, 51). Moreover, the concentrations of estrogen and progesterone.
udder may remain completely collapsed until This rationale is based on observations that high
the fetus is removed and then the udder fills doses of estrogen (43) or estrogen and proges-
with secretions in a few days. Lactation is then terone (72) inhibit established lactation where-
comparable to those initiated by normal calving as small doses are stimulatory (65 for review).
(10). Udders of heifers and cows with regressed Since mammary secretions prepartum con-
udders show no evidence of filling prior to tain elevated concentrations of prolactin, pro-
abortion if this occurs 2 to 3 mo before end of gesterone, estrogens (Table 1), and probably
normal gestation. Lactation can be established other hormones (corticoids, growth hormone,
by milking, but total lactation yields are de- etc.), their removal could alter the hormonal
pressed and are proportional to stage of gesta- environment of secretory cells. This may affect
tion when abortion occurs (99). Such cows only timing of events associated with onset of
increase slowly to maximum daily rates (99), as lactation, but data available currently are inade-
do those induced to lactate by 7-day treatment quate to evaluate biological significance.
with E2/3 and P (33, 91). Rate of excretion of If roles assigned to progesterone and estro-
estrogen in urine of cows increased at time of gen regarding onset of lactation should be
abortion induced by ovariectomy (69), and in proven correct in a general way, then it is
two cases of spontaneous abortion (unpub- doubtful that their variations periparturiendy
lished). would be predictive of subsequent intensity of
Several anomalous factors require rationali- lactation or clearly associated with periparturi-
zation even though we cannot accept that ent variations in other hormones essential for
ensuing lactations are equivalent to that follow- function of the mammary gland. A more
ing birth. These anomalies include spontaneous promising approach may be to understand the
lactation in virgin goats (37) and lactation after mechanisms causing proliferation of alveoli and
udder stimulation (manual or suckled) of non- continued replication of their secretory cells
pregnant (5, 108) or pregnant heifers (105), or during pregnancy. This includes more research
a nonpregnant, dry ewe (88). It seems necessary on mammary receptors and, especially, on
to recognize the probable hormonal conse- factors controlling entry of precursors and
quences of mammary stimulation before onset steroids into mammary cells in vivo. It seems
of lactation by calving. Presumably, udder essential to recognize that regulation of a cell's
stimulation would increase vascularity as well as activity is dependent upon characteristics of its
cause additional release of oxytocin, prolactin, plasma membrane. Synergistic or inhibitory
and ACTH (19 for review). Under these condi- effects of steroids on intracellular functions

Journal of Dairy Science Vol. 60, No. 2

 REVIEW: HORMONES FOR MAMMOGENES1S AND LACTATION 165

seem under control of receptors and other 8:513.

mechanisms in plasma membranes which regu- 8 Benson, G. K., A. T. Cowie, C. P. Cox, D. S.
late uptake by cells. Therefore, rate and type of Flux, and S. J. Folley. 1955. Studies on the
hormonal induction of mammary growth and
intracellular activity in vivo should be depen- lactation in the goat. I1. Functional and morpho-
dent upon transport mechanisms, as well as logical studies of hormonally developed udders
upon temporal concentration gradients and with special reference to the effect of 'triggering'
interactions of essential hormones in intercellu- doses of oestrogen. J. Endocrinol. 13:46.
9 Buttle, H. L., and Forsyth, I. A. 1976. Placental
lar spaces and in or upon the plasma membrane.
lactogen in the cow. J. Endocrinol. 68:141.
Regardless of what the in vivo mechanisms of 10 Callahan, C. J., J. F. Fessler, R. E. Erb, E. D.
c o n t r o l m a y be, greater mass o f s e c r e t o r y tissue Plotka, and R. D. Randel. 1969. Prolonged
o u g h t to be associated w i t h i n c r e a s e d p o t e n t i a l gestation in a Holstein-Friesian cow. Clinical and
for milk yield. S u b n o r m a l l a c t a t i o n curves, a n d reproductive steroid studies. Cornell Vet. 49: 370.
11 Catchpole, H. R., W. R. Lyons, and W. M. Regan.
yields a f t e r a b o r t i o n a n d t r e a t m e n t o f n o n p r e g -
1933. Induction of lactation in heifers with the
n a n t , dry cows w i t h E2/3 a n d P to i n d u c e hypophyseal lactogenic hormone. Proc. Soc. Exp.
l a c t a t i o n s u p p o r t t h e latter. Cows n o r m a l l y do Biol. Med. 31:301.
n o t a p p e a r to c o n t i n u e s e c r e t o r y cell prolifera- 12 Ceriani, R. L. 1970. Fetal mammary gland
t i o n a f t e r calving (4 for review). Moreover, it is differentiation in vitro in response to hormones.
1. Morphological findings. Develop. Biol. 21:506.
u n k n o w n if s e c r e t o r y cells are r e p l a c e d d u r i n g 13 Ceriani, R. L. 1970. Fetal mammary gland
l a c t a t i o n or if t h e y c o n t i n u e to increase for a differentiation in vitro in response to hormones.
longer p e r i o d f o l l o w i n g a b o r t i o n , h o r m o n a l l y II. Biochemical findings. Develop. Biol. 21:530.
i n d u c e d l a c t a t i o n , or o t h e r a n o m a l o u s c i r c u m - 14 Chatterton, R. T., Jr., A. J. Chatterton, and L.
HeUman. 1969. Metabolism of progesterone by
stances t h a t f o l l o w calving. W h a t e v e r t h e case in the rabbit mammary gland. Endocrinology
the n a t u r a l state, a t t e m p t s to s t i m u l a t e existing 85:16.
l a c t a t i n g cells or to i n d u c e n e w s e c r e t o r y cells 15 Chew, B. P., H. F. Keller, R. E. Erb, and P. V.
d u r i n g l a c t a t i o n s h o u l d be c o n t i n u e d . Finally, Malven. 1976. Endocrinology of retained fetal
membranes in cows. J. Anirn. Sci. 43:278.
we s h o u l d r e m a i n o p t i m i s t i c t h a t practical
(Abstr.)
t e c h n i q u e s can be d e v e l o p e d to i n d u c e reliably 16 Collier, R. J., D. E. Banman, W. J. Croom, and R.
full l a c t a t i o n w i t h h o r m o n e s to salvage cows L. Hays. 1976. Lactogenesis in explant cultures
t e m p o r a r i l y infertile. of cow mammary tissue. Page 59 in Proc. 71st
Ann. Meeting, Amer. Dairy Sci. Ass., Champaign,
1L 61820. (Abstr.)
REFERENCES
17 Collier, R. J., D. E. Bauman, and R. L. Hays.
1 Akers, R. M., C. W. Heald, and T. L. Bibb. 1976. 1975. Milk production and reproductive perform-
Stimulatory effect of prepartum milk removal on ance of cows hormonally induced into lactation.
bovine lactogenesis measured cytologically. Page J. Dairy Sci. 58:1524.
58 in Proc. 71st Ann. Meeting, Amer. Dairy Sci. 18 Collier, R. J., W. J. Croom, D. E. Bauman, R. L.
Ass., Champaign, IL 61820. (Abstr.) Hays, and D. R. Nelson. 1976. Cellular studies of
2 Ancel, P., and P. Bouin. 1909. Action du corps mammary tissue from cows hormonally induced
juane vrai sur la gland mammaire. Comp. rend. into lactation: Lactose and fatty acid synthesis.
Soc. de Biol. 66:605. J. Dairy Sci. 59:1226.
3 Ancel, P., and P. Bouin. 1911. Recherches sur les 19 Convey, E. M. 1974. Serum hormone concentra-
fonctions du corps juane gestatif, lI. Sur le tions in ruminants during mammary growth,
determinisme du development de la gland mam- lactogenesis, and lactation: A review. J. Dairy
maire an tours de la gestation. J. Physiol. et Path. Sci. 57:905.
Gen. 13:31. 20 Convey, R. M., H. A. Tucker, V. G. Smith, and J.
4 Anderson, R. R. 1974. Endocrinological Control. Zolman. 1973. Bovine prolactin, growth hor-
Page 97 in B. L. Larson and V. R. Smith, ed. mone, thyroxine and corticoid response to thyro-
Lactation: A comprehensive treatise, Vol. 1. tropin-releasing hormone. Endocrinology 92:471.
Academic Press, Inc., New York and London. 21 Cowie, A. T. 1970. Influence of hormones on
5 Asdell, S. A. 1931. Recent developments in the mammary growth and milk secretion. Page 123 in
field of sex hormones. CorneU Vet. 21:147. I. R. Falconer, ed. Lactation. Butterworths,
6 Atger, M., E. E. Baulieu, and E. Milgrom. 1974. London.
An investigation of progesterone receptors in 22 Cowie, A. T., G. S. Knaggs, and J. S. Tindal.
guinea pig vagina, uterine cervix, mammary 1964. Complete restoration of lactation in the
glands, pituitary and hypothalamus. Endocrinolo- goat after hypophysectomy. J. Endocrinol.
gy 94:161. 28: 267.
7 Bash, K. 1909. Uber experimentelle ausliSsung 23 Cowie, A. T., and J. S. Tindal. 1971. The
von milchabsonderung. Monatschr. f. Kinderh. physiology of lactation. Edward Arnold Ltd.,

Journal of Dairy Science Vol. 60, No. 2

166 ERB

London. extracts of pituitary glands from different spe-

23aCroom, W. J., R. J. Collier, D. E. Bauman, and R. cies. J. Endocrino[. 4:212.
L. Hays. 1976. Cellular studies of mammary 38 Frank, R. T., and A. Unger. 1911. An experi-
tissue from cows hormonally induced into lacta- mental study of the causes which produce growth
tion: Histology and ultrastructure. J. Dairy Sci. of the mammary gland. Archly. Int. Med. 7:812.
59:1232. 39 Frantz, W. L., J. H. MacIndoe, and R. W.
24 D'Amico, M. F., R. E. Erb, and P. V. Malven. Turkington. 1974. Prolactin receptors: Charac-
1976. Effect of TRIt on induction of lactation in teristics of the particulate fraction binding ca-
ewes pretreated with ovarian steroids. Page 141 pacity activity. J. Endocrinol. 60:485.
in Proc. 71st Ann. Meeting, Amer. Dairy Sci. 40 Gardner, D. G., and J. L. Witdiff. 1973. Specific
Ass., Champaign, IL 61820. (Abstr.) estrogen receptors in the lactating mammary
25 DeFremery, P. 1936. On the influence of differ- gland of the rat. Biochem. 12: 3090.
ent hormones on lactation. J. Physiol. 87:50 P. 41 Gorewit, R. C., and H. A. Tucker. 1976. Corti-
(Abstr.) cold binding in mammary tissue slices from
26 Denamur, R. 1971. Hormonal control of [acto- lactating cows. J. Dairy Sci. 59: 232.
genesis. J. Dairy Res. 38:237. 42 Halban, J. 1900. Uber den Einfluss der Ovarien
27 DeSombre, E. R. 1972. Mechanism of action of auf die Entwichlung des Genitales. Monatschr. f.
the female sex hormones. Ann. Rev. Biochem. Geburtsh. u. Gyn~ik. 12:496.
41:203. 43 Hammond, J., and F. 1". Day. 1944. Oesttogen
28 Dobson, H., and P. 19. G. Dean. 1974. Radloim- treatment of cattle: induced lactation and other
munoassay of oestrone, oestradiol-17a and 17fl in effects. J. Endocrinol. 4:53.
bovine plasma during the oestrus cycle and last 44 Hammond, J., and F. H. A. Marshall. 1914. The
stage of pregnancy. J. Endocrinol. 61:479. functional correlation between the ovaries, uter-
29 Ebner, K. E., and F. L. Schanbacher. 1974. us, and mammary #ands in the rabbit with
Biochemistry of lactose and related carbohy- observations on the estrous cycle. Proc. Royal
drates. Page 77 in B. L. Larson and V. R. Smith, Soc. B. 87:422.
ed. Lactation: A comprehensive treatise, Vol. II. 45 Hancock, J., P. J. Brumby, and C. W. Turner.
Academic Press Inc., New York and London. 1954. Hormonal induction of lactation in identi-
30 Edgerton, L. A., and H. D. Hafs. 1973. Serum cal twin dairy cattle. N. Z. J. Sci. Tech., Sec. A.
luteinizing hormone, prolactin, g[ucocotticoid, 36:111.
and progestin in dairy cows from calving to 46 Hartman, P. E., P. Trevethan, and J. N. Shelton.
gestation. J. Dairy Sci. 56:451. 1973. Progesterone and oestrogen and initiation
31 Erb, R. E., B. P. Chew, H. F. Keller, and P. V. of lactation in ewes. J. Endocrinol. 59:249.
Malven. 1977. Effect of hormonal treatments 47 Heald, C. W. 1974. Hormonal effects on mam-
prior to lactation on hormone in blood plasma, mary cytology. J. Dairy Sci. 57:917.
milk, and urine during early lactation: Progester- 48 Heap, R. B., and J. L. LinzeU. 1966. Arterial
one, estrogens, and prolactin. J. Dairy Sci. (In concentration, ovarian secretion and mammary
press). uptake of progesterone in goats during the
32 Erb, R. E., H. A. Garverick, R. D. Randel, B. L. reproductive cycle. J. Endocrinol. 36:389.
Brown, and C. J. Cailahan. 1976. Profiles of 49 Hindery, G. A., and C. W. Turner. 1964. Effect
reproductive hormones associated with fertile of repeated injections of estrogen on milk yield
and nonfertile inseminations of dairy cows. Ther- of nulliparous heifers. J. Dairy Sci. 47:1092.
iogenology 5: 227. 50 Hoffmann, B., D. Schams, T. Gimenez, M. L.
33 Erb, R. E., P. V. Malven, E. L. Monk, T. A. Ender, C. Hermann, and H. Karg. 1973. Changes
Mollett, K. L. Smith, F. L. Schanbacher, and L. of progesterone, total oestrogens, corticosteroids,
B. Willett. 1976. Hormone induced lactation in prolactin and LH in bovine peripheral plasma
the bovine. IV. Relationships between lactational around parturition with special reference to the
performance and hormone concentrations in effect of exogenous corticoids and a prolactin
blood plasma. J. Dairy Sci. 59:1420. inhibitor, respectively. Acta Endocrinol. 73:385.
34 Erb, R. E., E. L. Monk, T. A. Mollett, P. V. 51 Holm, L. W., and R. V. Short. 1962. Progester-
Malven, and C. ]. Caliahan. 1976. Estrogen, one in the peripheral blood of Guernsey and
progesterone, prolactin and other changes associ- Friesian cows during prolonged gestation. J.
ated with bovine lactation induced with esrradi- Reprod. Fertil. 4:137.
ol-17fl and progesterone. J. Anim. Sci. 42:644. 52 Horwitz, K. B., and W. L. McGuire. 1975.
35 Evans, E. E. 1932. Initiation of copious milk Specific progesterone receptors in human breast
secretion in virgin goats by anterior pituitary. cancer. Steroids 25:497.
Proc. Soc. Exp. Biol. ivied. 30:1372. 53 Hudson, S., M. Mullford, W. G. Whittlestone, and
36 Fellner, O. O. 1913. Experimentelle untersuch- E. Payne. 1976. Bovine plasma corticoids during
ungen ilber die wirkung yon gewebsextrakten aus parturition. J. Dairy Sci. 59:744.
der Plazenta und den weiblichen Sexualorganen 54 Hunter, D. L., R. E. Erb, R. D. Randel, H. A.
auf das Genitale. Archly. f. Gynec. 100:641. Garverick, C. J. Callahan, and R. B. Harrington.
37 Folley, S. J., F. H. Malpress, and F. G. Young. 1970. Reproductive steroids in the bovine. I.
1945. The galactopoietic action of pituitary Relationships during late gestation. J. Anim. Sci.
extracts in lactating cows. 3. Comparison of 30:47.

Journal of Dairy Science Vol. 60, No. 2

 REVIEW: HORMONES FOR MAMMOGENESIS AND LACTATION 167

55 lngalls, W. G., E. M. Convey, and H. D. Hafs. 70 Mellin, T. N., and R. E. Erb. 1965. Estrogens in
1973. Bovine serum LH, GH and prolactin during the b o v i n e - a review. J. Dairy Sci. 48:687.
late pregnancy, parturition and early lactation. 71 Mixner, J. P., and C. W. Turner. 1943. The
Proc. Soc. Exp. Biol. Med. 143:161. mammogenic hormones of the anterior pituitary
56 Johke, T., H. Fuse, and M. Oshima. 1971. gland. II. The lobule-aiveolar growth factor. Mo.
Changes in plasma prolactin level during late Agr. Exp. Sta. Res. Bull. 378.
pregnancy and early lactation in the goat and the 72 Mollett, T. A., R. E. Erb, E. L. Monk, and P. V.
cow. Japan J. Zootech. Sci. 42:173. Malven. 1976. Changes in estrogen, progesterone,
57 Karg, H., D. Schams, and V. Reinhardt. 1972. prolactin and lactation traits associated with
Effects of 2-Br-~-ergocryptine on plasma prolac- injection of estradiol-17# and progesterone into
tin level and milk yield in cows. Experientia lactating cows. J. Anim. Sci. 42:655.
28: 574. 73 Monk, E. L., R. E. Erb, and T. A. Mollett. 1975.
58 Keller, H. F., B. P. Chew, R. E. Erb, and P. V. Relationships between immunoreactive estrone
Malven. 1976. Hormonal differences associated and estradiol in milk, blood, and urine of dairy
with failure to induce lactation in cows with cows. J. Dairy Sci. 58: 34.
ovarian steroids. Page 102 in Proc. 71st Ann. 74 Moss, G. E., R. G. Sasser, V. L. Estergreen, S. A.
Meeting, Amer. Dairy Sci. Ass., Champaign, IL Becker, and S. L. Davis. 1975. Effect of TRH on
61820. (Abstr.) induced lactation. J. Anita. Sci. 41: 370. (Abstr.)
59 Kinsella, J. E., and C. W. Heald. 1972. Na 1-~4C 75 Narendran, R., R. R. Hacker, T. R. Batra, and E.
stearate and Na 2-~4C acetate metabolism and B. Burnside. 1974. Hormonal induction of lacta-
morphological analysis of late prepartum bovine tion in the bovine: Mammary gland histology and
mammary tissue. J. Dairy Sci. 55:1085. milk composition. J. Dairy Sci. 57:1334.
60 Klein, J. W., and T. E. Woodward. 1943. Influ- 76 Nickerson, S. C., C. W. Heald, and T. L. Bibb.
ence of length of dry period on the quantity of 1976. Cytological effects of hormones and plas-
milk produced in the subsequent lactation. J. ma on bovine mammary tissue in vitro. Page 59
Dairy Sci. 26:705. in Proc. 71st Ann. Meeting, Amer. Dairy Ass.,
61 Knaner, E. 1900. Die Ovarientransplantation. Champaign, IL 61820. (Abstr.)
Arch. f Gyn~kol. 60: 322. 77 O'Keefe, E., and P. Cuatrecasas. 1974. Insulin
62 Koprowski, J. A., and H. A. Tucker. 1973. Serum receptors in murin¢ mammary cells: comparison
prolactin during various physiological states and in pregnant and nonpregnant animals. Biochim.
its relationship to milk production in the bovine. Biophys. Acta 343:64.
Endocrinology 92:1480. 78 Parkes, A. S. 1929. The functions of the corpus
63 Lane-Calyton, J. E., and E. H. Starling. 1906. An luteum. III. Factors concerned in the develop-
experimental inquiry into factors which deter- ment of the mammary glands. Proc. Roy. Soc. B.,
mine the growth and activity of the mammary London 107:188.
glands. Proc. Roy. Soc. B. 77: 505. 79 Peeters, G., and L. Massart. 1974. Implants of
64 Lyons, W. R., C. H. Li, and R. E. Johnson. 1958. synthetic oestrogens in the udders of sheep. J.
The hormonal control of mammary growth. Rec. Endocrinol. 5:166.
Prog. Hormone Res. 14:219. 80 Riddle, O. 1942. Lactogenic and mammogenic
65 Meites, J. 1961. Farm animals: hormonal induc- hormones. Page 67 in Glandular physiology and
tion of lactation and galactopoiesis. Page 321 in therapy. American Medical Ass., Chicago, IL.
S. Kon and A. T. Cowie, ed. Milk: The mammary 81 Robertson, H. A. 1974. Changes in the concen-
gland and its secretion. Vol. II. Academic Press tration of unconjugated oestrone, oestradiol-17a
Inc., New York and London. and oestradiol-17/~ in the maternal plasma of the
66 Meites, J., and C. W. Turner. 1942. Studies pregnant cow in relation to the initiation of
concerning the mechanism controlling the initia- parturition and lactation. J. Reprod. Fert. 36:1.
tion of lactation at parturition. I. Can estrogen 82 Saacke, R. G., and C. W. Heald. 1974. Cytologi-
suppress the lactogenic hormone of the pituitary? cal aspects of milk formation and secretion. Page
Endocrinology 30: 711. 147 in B. L. Larson and V. R. Smith, ed.
67 Meites, J., and C. W. Turner. 1942. Studies Lactation: A comprehensive treatise, Vol. II.
concerning the mechanism controlling the initia- Academic Press, Inc., New York and London.
tion of lactation at parturition. III. Can estrogen 83 Schams, D., and H. Karg. 1972. The immediate
account for the precipitous increase in the response of the plasma prolactin level to oestro-
lactogen content of the pituitary following par- gen infusions in dairy cows. Acta Endocrinol.
turition. Endocrinology 30:726. 69:47.
68 Meites, J., and C. W. Turner. 1948. Studies 84 Schams, D., V. Reinhardt, and H. Karg. 1972.
concerning the induction and maintenance of Effects of 2-Br-c~-ergocryptine on plasma prolac-
lactation. II. The normal maintenance and experi- tin levels during parturition and onset of lacta-
mental inhibition and augmentation of lactation. tion in cows. Experientia 28:697.
Mo. Agr. Exp, Sta. Res. Bull. 416. 85 Sehanbacher, F. L., and K. L. Smith. 1975.
69 Mellin, T. N. 1964. Bovine urinary estrogen Formation and role of unusual whey proteins and
excretion before and after normal and induced enzymes: Relation to mammary function. J.
parturition. Ph.D. Thesis, Purdue University, W. Dairy Sci. 58:1048.
Lafayette, IN. 86 Schmitt, D., H. A. Garverick, E. C. Mather, J. D.

Journal of Dairy Science Vol. 60, No. 2

168 ERB

Sikes, B. N. Day, and R. E. Erb. 1975. Induction mouse. Page 327 in B. L. I.arson and V. R.
of parturition in dairy cattle with dexamethasone Smith, ed. Lactation: A comprehensive treatise,
and estradiol benzoate. J./Maim. Sci. 40:261. Vol. I. Academic Press, Inc., New York and
87 Shyamala, G. 1973. Specific cytoplasmic gluco- London.
corticoid hormone receptors in lactating mare- 103 Tucker, H. A. 1974. General endocrinolo#cal
mary #ands. Biochemistry 12: 3085. control of lactation. Page 277 in B. L. Larson and
88 Sitarz, N. E., R. E. Erb, P. V. Malven, T. A. V. R. Smith, ed. Lactation: A comprehensive
Mollett, and E. L. Monk. 1976. Estrogen, proges- treatise, Vol. 1. Academic Press, Inc., New York
terone, prolactin, milk composition and other and London.
changes associated with hormonal induction of 104 Tucker, H. A., B. L. Larson, and J. Gorski. 1971.
lactation in nonpregnant ewes. (Unpublished). Cortisol binding in cultured bovine mammary
89 Sukarda, J., and J. Bilek. 1975. Response of cells. Endocrinology 89:152.
mammary tissue from pregnant goats to prolactin 105 Tucker H. A., and J. Meites. 1965. Induction of
and growth hormone in organ culture. J. Endo- lactation in pregnant heifers with ~-fluoropred-
crinol. 67:129. nisolone acetate. J. Dairy Sci. 48:403.
90 Smith, K. L, D. R. Redman, and F. L. Schan- 106 Turkington, R. W., and R. L. Hill. 1969. Lactose
bacher. 1973. Efficacy of 17~estradiol and pro- synthetase: progesterone inhibition of the induc-
gesterone treatment to initiate lactation in infer- tion of aqactalbumin. Science 163:1458.
tile cows. J. Dairy Sci. 56:657. (Abstr.) 107 Turners, C. D., and J. T. Bagnara. 1971. Page 512
91 Smith, K. L., and F. L. Schanbaeher. 1973. in General Endocrinology, 5th ed. W. B. Saunders
Hormone induced lactation in the bovine. I. Co., Philadelphia.
Lactational performance following injections of 108 Turner C. W. 1931. The development of the
1713-estradiol and progesterone. J. Dairy Sci. mammary #and as indicated by the initiation and
56:738. increase in the yield of secretion. Mo. Agr. Exp.
92 Smith, K. L., and F. L. Schanbacher. 1974. Sta. Res. Bull. 156.
Hormone induced lactation i n the bovine. 1I. 109 Turner C. W. 1939. The mammary glands. Page
Response of nulligravida heifers to modified 740 in E. Allen, ed. Sex and internal secretions,
estrogen-progesterone treamaent. J. Dairy Sci. 2nd edition. Williams and Wilkens Co., Baltimore,
57:296. MD.
93 Smith, R. D., W. Hansel, and C. E. Coppock. 110 Turner C. W. 1959. The experimental induction
1976. Plasma growth hormone and insulin during of growth of the cow's udder and the initiation
early lactation in cows fed silage based diets. J. of milk secretion. Mo. Agr. Exp. Sta. Res. Bull.
Dairy Sci. 59:248. 697.
94 Smith, V. G., T. W. Beck, E. M. Convey, and H. 111 Turner, C. W., and A. H. Frank. 1930. The effect
A. Tucker. 1974. Bovine serum prolaetin, growr_h of estrus producing hormone on the growth of
hormone, cortisol, and milk yield after ergocryp- the mammary gland. Mo. Agr. Exp. Sta. Res.
tine. Neuroendocrinol. 15:172. Bull. 145.
95 Smith, V. G., L. A. Edgerton, H. D. Hafs, and E. 112 Turner, C. W., and A. H. Frank. 1931. The
M. Convey. 1973. Bovine serum estrogens, pro- relations between the estrus producing hormone
gesdns and glucocorticoids during late pregnancy, and a corpus luteum extract on the growth of the
parturition and early lactation. J. Anita. Sci. mammary gland. Science 73:295.
36:391. 113 Turner C. W., and W. U. Gardner. 1931. The
96 Steinach, E., M. Dohrn, W. SchoeUer, W. Hoiweg, relation of the anterior pituitary hormones to the
and W. Faure. 1928. 0bet die biologischen development and secretion of the mammary
wirkungen des weiblichen Sexualhormons. Arch. gland. Mo. Agr. Exp. Sta. Bull. 206.
feur. Gesante Physiol 219: 306. 114 Turner, C. W., R. Williams, and G. A. Hindery.
97 Stricter, P., and F. Grueter. 1928. Action du lobe 1963. Growth of the udders of dairy heifers as
anterior de l'hypophyse sur la montee laiteuse. measured by milk yield and desoxyribonucleic
Comp. Rend. Soc. de Biol. 99:1978. acid. J. Dairy Sci. 46:1390.
98 Sud, S. C., H. A. Tucker, and J. Meites. 1968. 115 Turner, C. W., H. Yamamoto, and H. L. Ruppert,
Estrogen-progesterone requirements for udder Jr. 1956. The experimental induction of growth
development in ovariectomized heifers. J. Dairy in the cow's udder and the initiation of milk
Sci. 51~210. secretion. J. Dairy Sci. 39:1717.
99 Swanson, E. W. 1970. Effect of abortions and 116 Welty, F. K., K. L. Smith, and F. L. Sehanbacher.
short gestations on lactation. J. Dairy Sci. 1976. Lactofertin concentration during involu-
53:381. tion of the bovine mammary gland. J. Dairy Sci.
100 Sykes, J, F., and T. R. Wrenn. 1951. Hormonal 59:224.
development of mammary tissue in dairy heifers. 117 Willett, L. B., K. L. Smith, F. L. Schanbacher, R.
J. Dairy Sci, 34:1174. E. Erb, and P. V. Malven. 1976. Hormone
101 Topper, ¥. J. 1970. Multiple hormone interac- induced lactation in the bovine. 1II. The dynam-
tions in the development of mammary gland in ics of injected endogenous hormones. J. Dairy
vitro. Rec. Prog. Hormone Res. 26:287. Sci. 59: 504.
102 Topper, Y. J., and T. Oka. 1974. Some aspects of 118 Williams, R., and C. W. Turner. 1961. Effects of
mammary gland development in the mature increased levels of ovarian hormones and dura-

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tion of treatment on the experimental induction J. Dairy Sci. 45:1248.

of growth of the cow's udder. J. Dairy Sci. 120 Voytovich, A. E., and Topper, Y. T. 1967.
44:524. Hormone-dependent differentiation of immature
119 Williams, R., and C. W. Turner. 1962. Study of mouse mammary gland in vitro. Science
successive experimental lactations in dairy coy 158:132b.

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