Journal of Equine Veterinary Science 35 (2015) 343–353

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Journal of Equine Veterinary Science

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Review Article

Prolactin in the Horse: Historical Perspective, Actions

and Reactions, and Its Role in Reproduction
Donald L. Thompson Jr. *, Erin L. Oberhaus
School of Animal Sciences, Louisiana Agricultural Experiment Station, LSU AgCenter, Baton Rouge, LA

a r t i c l e i n f o a b s t r a c t

Article history: Prolactin is a hormone with diverse biological effects in various species. The secretion of
Received 16 February 2015 prolactin in horses is affected by season, thyrotropin-releasing hormone, dopaminergic
Accepted 19 March 2015 and antidopaminergic agents, exercise and stressful stimuli, meal feeding, estrogen
Available online 8 April 2015
treatment, and antiopioidergic agents. The need of prolactin for mammary growth and
lactation in mares has been elucidated from research on endophyte-infected fescue
Keywords:
grazing and its associated problems in late gestation. This has led to the development of
Prolactin
treatments for fescue toxicity and protocols for inducing lactation in nonpregnant mares.
Season
Dopaminergic Treatment with prolactin has demonstrated that it is involved with the shedding of the
Hair shedding winter coat in spring (increasing concentrations) and likely with the growth of the winter
Lactation coat in the fall (decreasing concentrations). Prolactin secretion is highly correlated with
Ovarian recrudescence the photoperiod and is low in winter and high in summer. The coincidence of rising
prolactin concentrations in blood with the onset of ovarian activity during the spring
transition period in mares led to research showing that prolactin treatment, or inducement
of high prolactin secretion by means of antidopaminergic agents, in winter can induce
ovarian activity and ovulation in seasonally anovulatory mares. The combination of a small
amount of estrogen in addition to an antidopaminergic agent has been shown to produce a
synergy resulting in very high prolactin concentrations in blood. The results of 39 years of
research on equine prolactin illustrate nicely how the gradual accumulation of knowledge
derived from basic research questions can generate applied solutions to real-world
problems.
Ó 2015 Elsevier Inc. All rights reserved.

1. Historical PerspectivedDiscovery, Description, and
Functional Variabilities Among Species
Prolactin in the horse is a 199-amino acid peptide
hormone produced and secreted by the equine adenohy-
pophysis (glandular portion of the pituitary). Stricker and
Grueter [1], in 1928, first described the stimulatory activity
of extracts of bovine adenohypophyses on rabbit mammary
glands, and in 1933, Riddle et al [2] reported the stimu-
Approved for publication by the Director of the Louisiana Agricultural
Experiment Station as manuscript number 2015-230-20995.
* Corresponding author at: Donald L. Thompson, Jr., School of Animal
Sciences, Louisiana State University, Baton Rouge, LA 70803-4210.
E-mail address: dthompson@agctr.lsu.edu (D.L. Thompson).
lation of pigeon crop sacs by a substance in similar extracts
and coined the term “prolactin” due to its milk-inducing
effects.
Equine prolactin was first isolated and partially char-
acterized by Chen et al [3] in 1979 and further in 1983 by Li
and Chung [4]. Li and Chung [4] suggested that equine
prolactin differs from that of other farm species in that it is
one amino acid longer and contains only four cysteine
residues rather than six common in other species, due to its
lack of an NH2-terminal disulfide loop [4]. More recently,
Lehrman et al [5] reported that equine prolactin contained
the typical six cysteine residues rather than four. The
amino acid sequence, which contributes significantly to its
immunologic (antigenic) properties, of equine prolactin is
most similar (homologous) to canine (94%), porcine (93%),

0737-0806/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jevs.2015.03.199
344 D.L. Thompson Jr., E.L. Oberhaus / Journal of Equine Veterinary Science 35 (2015) 343–353
and fin whale (91%) prolactin compared with the human
(78%), bovine (76%), ovine (75%), or mouse (57%) hormones
[5–7]. In an immunocytochemical study, Rahmanian et al
[8] reported that prolactin could be localized to two specific
lactotrope types in equine adenohypophyseal tissue (types
I and II, distinguished by size and secretion granule size
and distribution). Lactotropes comprised between 5% and
16% of the cells in the gland. Prolactin was also found
to colocalize with growth hormone in cells commonly
referred to as mammosomatotropes, and these comprised
an average of 6% to 16% of all cell types.
Extrapituitary sources of prolactin have been suggested
in other species, and King et al [9], using immunocyto-
chemical techniques, reported a localization of prolactin in
the equine ovary in antral follicles, the ovulation fossa, and
the corpus luteum. Moreover, they were also able to detect
preprolactin cDNA in samples of follicular and luteal tissue,
suggesting a potential for prolactin production in those
tissues.
Prolactin is somewhat unique among pituitary hor-
mones in its degree of variability of biological effects across
species. Prolactin has been implicated in areas as diverse as
growth of tadpoles and metamorphosis into frogs, luteal
function and spermatogenesis in rodents, osmotic regula-
tion in teleost fishes, modulation of immune system cells in
various species, parenting and migration behaviors in birds
and mammals, molting and regrowth of hair in winter
foxes, and establishment of embryonic diapause in mar-
supials [10]. Thus, students of endocrinology, if asked
“What does prolactin do?” must first ask in response “In
what species?” obligatory effects of prolactin in one spe-
cies, for example, its requirement for normal luteal function
in the ewe [11], will not necessarily hold true in a different
species. Given this diversity, the focus of this review will
hereafter be on characteristics of prolactin, factors affecting
its secretion, and its documented effects on physiological
functions specifically derived from research on horses.
2. Measurement and Secretory Patterns
2.1. Measurement
The earliest publications concerning equine prolactin,
based on the U.S. National Library of Medicine database,
appeared in the 23rd Supplement of the Journal of Repro-
duction and Fertility as a result of presentations by Dr. Terry
Nett at the First International Symposium on Equine
Reproduction in Cambridge, UK, in July of 1974 [12]. Pro-
lactin concentrations were described as high and variable
for pregnant and postpartum mares, although the specifics
of the assay (antiserum and iodinated preparation) were
not given in the manuscript. It was not until 10 years later
that Roser et al [13] developed and reported on a homol-
ogous radioimmunoassay (RIA) for equine prolactin. This
opened the doors for research into equine prolactin, which
blossomed thereafter. In 1986, Worthy et al [14] also re-
ported data for prolactin in pregnant and postpartum pony
mares, based on a homologous RIA, and the results were
very similar to those of Nett et al [12]. Also in 1986,
Thompson et al [15] reported on the use of an equine–
canine RIA to measure equine prolactin. Subsequently, in
1991, that group developed and validated an RIA based on
antiserum against porcine prolactin that they have used in
all subsequent research [16]. Although variant in compo-
nents, the various assays for equine prolactin have provided
fairly consistent and biologically logical results across the
numerous laboratories, with the exception of two reports
[17,18], in which it was reported that thyrotropin-releasing
hormone (TRH) did not affect prolactin secretion.
2.2. Secretory Pattern
Prolactin concentrations in horses at rest are relatively
constant over time, except for occasional irregular pulses or
episodes superimposed on the basal concentrations. Roser
et al [19] described the episodic release of prolactin in cyclic
mares at the same meeting where Worthy et al [20]
reported occasional high prolactin concentrations in
mares when secretion seemed otherwise basal. Thompson
et al [21] measured prolactin in plasma samples drawn
every 15 minutes from four mares housed indoors and
reported that, superimposed over a declining baseline,
there occurred 0, 1, 3, and 3 peaks, or surges, in prolactin in
the 8-hour period. In contrast to those in the nonpregnant
mare, Nett et al [22] reported that prolactin concentrations
in mares during gestation were extremely variable with
no clear pattern of fluctuation. Similarly, Cahill et al [23]
described prolactin concentrations in lactating mares as
having long episodic bursts, whereas Worthy et al [20]
described them as high and irregular.
One situation where episodes in prolactin secretion
seem to occur consistently is in late diestrus and the peri-
ovulatory period. Worthy et al [20] first described a marked
rise in prolactin concentrations shortly before the onset of
estrus in mares during fall estrous cycles, although this rise
was less obvious in cycles in spring and summer. Irvine et al
[24] reported a similar rise in prolactin associated with
luteolysis in mares in autumn transition, and the occur-
rence was the same for ovulatory and nonovulatory cycles.
Shand et al [25] induced luteolysis with prostaglandin-F2a
(PGF2a) and reported similar pulses in prolactin that
occurred first around the time of the nadir of progesterone
concentrations. King et al [26] also reported higher plasma
prolactin concentrations in mares from 1 day before to 1
day after ovulation relative to the other days in the rest of
the estrous cycle. Moreover, they reported follicular fluid
prolactin concentrations of similar magnitude [26]. Ginther
and Beg [27] looked at the prolactin response relative to the
first naturally occurring PGF2a metabolite peak during
luteolysis and found it to be on the ascending side of that
peak. Subsequently, Ginther et al [28] suggested that the
pulses in prolactin occurring around the time of luteolysis
were in fact driven by the pulses in PGF2a occurring at that
time, as opposed to the other way around.
Although endogenous pulses of prolactin occur around
the time of luteolysis, their possible effects on luteolysis or
ovulation are unknown. Becker and Johnson [29] first
tested the hypothesis that prolonged hyperprolactinemia
might affect the timing of ovulation or corpus luteum
formation in mares. Hyperprolactinemia was produced
with frequent metoclopramide injections either on day 17
(follicular phase) or 11 (diestrus). Treatment increased
 D.L. Thompson Jr., E.L. Oberhaus / Journal of Equine Veterinary Science 35 (2015) 343–353
prolactin concentrations consistently but had no effect on
time to ovulation, time to luteolysis, or time of luteal for-
mation. Similarly, Martínez Boví et al [30] treated mares
with sulpiride every 12 hours beginning in early estrus and
reported no effect on time to ovulation.
2.3. Season
Johnson [31] was the first to report the seasonal pattern
of serum prolactin concentrations in horses. In that study,
prolactin concentrations were highest during the summer
and lowest in winter. That agreed well with what had been
reported in other species up to that point. The seasonal
pattern of prolactin has been confirmed many times over,
both in serum and pituitary [20,32,33], in the prolactin
response to TRH [15,34], and in the amount of prolactin
secreted by perifused pituitary cells [35]. In horses sampled
from birth to maturity [36], the seasonal pattern previously
described for adult horses by others was indeed evident,
and prolactin concentrations achieved in the first summer
were robust and just as high as those achieved in the sec-
ond summer of life.
Following up on his descriptions of seasonal patterns of
prolactin secretion, Johnson [34] demonstrated that sub-
jecting mares to 16 hours of light per day via supplemental
lighting starting in either September or December caused a
rise in prolactin concentrations, and the response was most
rapid in September. Johnson and Malinowski [37], in
similar studies, reported that both a 16-hour light (L):8-
hour dark (D) photoperiod and a 10L:8D:2L:4D photope-
riod stimulated prolactin concentrations in seasonally
anestrous mares. These experiments confirmed the role of
photoperiod (long days in summer and short days in
winter) in the regulation of the seasonal prolactin pattern.
3. Factors Affecting Prolactin Secretion
3.1. TRH Administration
An observation in horses that is very consistent with
those in other species is the stimulatory effect of TRH on
prolactin secretion. Johnson [34] was the first to describe
the stimulatory effect of TRH administration in the horse,
which was greater in summer than winter. Moreover,
Johnson and Becker [38] reported that the prolactin
response to TRH injection did not differ between mares in
estrus vs. diestrus. Lothrop et al [39] indicated that the
prolactin response to TRH in pregnant mares was similar
during gestation and the postpartum period, but during the
periparturient period, high basal prolactin concentrations
were associated with a minimal response to TRH. Colborn
et al [40] treated stallions in winter with sulpiride, a
dopamine antagonist, and found a fourfold increase in the
prolactin response to TRH in those stallions after treatment
relative to control stallions. Evans et al [35] perifused
pituitary cells from horses collected in different seasons of
the year and found a high correlation between prolactin
response to TRH exposure and hours of daylight when the
pituitaries were harvested.
Given its ability to release prolactin in most mamma-
lian species, TRH has been suggested over the years as a
345
possible “true” physiologic prolactin stimulatory factor, as
opposed to its effects being nonphysiologic or pharmaco-
logic (i.e., relatively large doses are needed to stimulate
prolactin secretion). Experiments studying this possibility
in horses have thus far indicated that TRH is not likely a
true physiologic regulator of prolactin secretion. Pruett
et al [41] fed stallions 6-n-propyl-2-thiouracil (PTU) daily
for 55 days to decrease thyroid activity. Relative to control
stallions, concentrations of thyroid-stimulating hormone
(TSH) in daily samples were elevated 10-fold in response
to the reduced negative feedback by thyroid hormones,
which was assumed to be driven by an increase in
endogenous TRH activity. Challenge with 10 mg of TRH
resulted in a greatly enhanced TSH response in PTU-fed
stallions but no alteration in the prolactin response.
Similarly, Alexander et al [42] used pituitary venous blood
sampling to assess prolactin and TSH secretion in peri-
ovulatory mares, half of which were previously made
hypothyroid by PTU feeding. Their conclusion was that
TRH is not a major factor controlling minute-to-minute
fluctuations in either TSH or prolactin secretion. And
lastly, Thompson et al [43] pretreated geldings with 50 mg
of thyroxine in biodegradable particles on day 0, which
raised plasma thyroxine concentrations in plasma for the
duration of the experiment. Compared with the responses
in control geldings, thyroxine treatment had no effect on
the prolactin responses to two exercise bouts on day 5, to
an injection of PGF2a on day 9, or to an injection of sul-
piride on day 13.
3.2. Dopaminergic and Antidopaminergic Compounds
The primary regulation of prolactin production and
secretion in horses is thought to be the same as described
in other species: via tonic suppressive activity of dopamine,
released into the hypothalamic-hypophyseal portal system
in the stalk-median eminence [44]. Johnson and Becker
[38] were the first to confirm that, in fact, administration of
bromocriptine, a dopamine agonist, reduced serum pro-
lactin concentrations in horses in May, when concentra-
tions were high, and that two dopaminergic antagonists,
metoclopramide and sulpiride, each alone stimulated an
immediate response in serum prolactin concentrations.
Subsequent reports of the use of perphenazine [45,46] and
domperidone [47] in mares confirmed their stimulatory
effects on prolactin secretion in the short term. Repeated
daily injections of sulpiride in vegetable shortening (to
slow its release) to stallions for 14 days in winter [40]
increased plasma prolactin concentrations in daily blood
more than sixfold, to levels comparable to those normally
found in stallions in summer. In contrast to those results in
stallions, the prolactin response to daily sulpiride injections
in oil administered to geldings in winter diminished rapidly
after the first injection [48], and only recovered when the
natural photoperiod began to rise. This difference between
the responses in geldings and stallions in winter was likely
the first indication of the need for the presence of either
testosterone or estradiol to synergize with the sulpiride
for maximal prolactin stimulation. This was eventually
confirmed by Kelley et al [49], who first described
the interaction between estradiol pretreatment and
346 D.L. Thompson Jr., E.L. Oberhaus / Journal of Equine Veterinary Science 35 (2015) 343–353
subsequent sulpiride administration in seasonally anovu-
latory mares.
The inhibitory effect of bromocriptine administration on
prolactin secretion in mares described by Johnson and
Becker [38] was found to be consistent in lactating horse
and pony mares [50], in which prolactin concentrations are
high. Administration of 100-mg bromocriptine suppressed
prolactin concentrations rapidly and kept them low for up
to 2–3 days. Similarly, Ireland et al [51] injected pregnant
pony mares with bromocriptine daily starting on day 295 of
gestation. Treatment reduced prolactin concentrations as
expected and resulted in extended gestation periods as
well as agalactia in treated mares after foaling. In stallions,
Thomson et al [52] used bromocriptine to block the pro-
lactin response to sexual excitement before seminal
collection. This resulted in no increase in seminal volume
compared with when stallions were sexually excited before
collection only.
Twice daily bromocriptine injections to mares in vernal
transition reduced plasma prolactin concentrations and
seemed to delay the growth of preovulatory follicles [46];
however, no effect was observed for date of first ovulation.
In a study with similar results (no effect on first ovulation),
Oberhaus et al [53] used a long-acting dopaminergic
compound, cabergoline, in every-10-day injections in a
slow-release vehicle to suppress prolactin concentrations
in mares starting on February 4. Identical injections of
cabergoline had been previously shown to suppress pro-
lactin secretion and the prolactin response to low-dose
sulpiride injections for at least 10 days [54,55]. For com-
parison, administration of 2 mg of pergolide, another
dopaminergic compound commonly used to treat pituitary
pars intermedia dysfunction in horses [56], reduced plasma
prolactin concentrations in geldings for only 6 hours when
given PO and only 24 hours when injected intramuscularly
in a slow-release vehicle formulation [54].
Naturally occurring compounds that mimic dopamine
and reduce prolactin concentrations in horses (ergot alka-
loids) are found in endophyte-infected tall fescue [57,58].
The detrimental effects of fescue grazing by pregnant mares
is well documented [59,60] and include extended gestation
lengths, thickened placenta, failure of the mammary glands
to develop, agalactia, and poor foal health or death. At least
some of these effects are believed to be mediated by the
reduction in plasma prolactin concentrations [61], although
a direct effect of the dopaminergic compounds cannot be
ruled out. Feeding domperidone during the last 30 days of
gestation can reverse the detrimental effects of fescue
grazing [47], and a commercial product (Equidone) is
available through licensed veterinarians. The detrimental
effects of fescue grazing can be mimicked by long-term
treatment with bromocriptine [51]. McDowell et al [62]
have shown that at least one direct effect of the dopami-
nergic compounds found in infected fescue is blood flow
restriction (vasoconstriction), and this may account for
some of the other problems with fescue grazing.
3.3. Exercise and Other Stressful Stimuli
Rabb et al [63] were the first to describe the stimulation
of plasma prolactin concentrations in stallions in response
to sexual excitement, with or without subsequent collec-
tion of semen. The response was rapid, with maximum
concentrations occurring within 6 minutes from the start of
exposure to an estrous mare. Colborn et al [16] confirmed
those observations and further showed that other forms of
stress (restraint via a twitch and brief exercise) also stim-
ulated a rise in plasma prolactin concentrations in stallions,
whereas injection of epinephrine did not. Thompson et al
[21] reported that the prolactin response to exercise was
similar in mares, stallions, and geldings when tested in
June. Sticker et al [64] compared the prolactin responses
to exercise between normal-fed mares and those feed
deprived for 73 hours. Although feed deprivation stimu-
lated the exercise-induced growth hormone response, it
had no effect on the immediate release of prolactin. Farris
et al [65] infused tryptophan at 100 mg/kg of body weight
into horses before exercise on a treadmill. Compared with
exercise bouts with no tryptophan infusion, plasma pro-
lactin concentrations were increased nearly threefold
before exercise and almost twofold early in exercise during
the tryptophan bouts.
When geldings were exercised for 5 minutes once
hourly for a total of four bouts [43], prolactin rises of similar
magnitude were observed for all four bouts. In that same
experiment, the same result held true for geldings pre-
treated with estradiol cypionate (ECP) to raise average
resting prolactin concentrations. Although preexercise
plasma prolactin concentrations were increased from
approximately 9–18 ng/mL, the net response to exercise,
which would be proportional to the amount of prolactin
released, was not changed.
McManus et al [66], in a study of photoperiodic vs.
metabolic signals that might be involved with the transi-
tion of mares into the breeding season, administered
2-deoxyglucose to mares in an effort to block normal
glucose utilization. Such treatment produced a perceived
hypoglycemia effect at the cellular level, and one response
to it was a rise in prolactin secretion. In 2010, Huff et al [67]
infused mares and geldings with Escherichia coli O55:B5
endotoxin (35 ng/kg of BW in 500 mL of saline over a
30-minute infusion), or saline only, in a switchback design
experiment. Endotoxin produced the expected rises in
rectal temperature, heart rate, respiration rate, and plasma
cortisol concentrations, as well as an extended period of
very high prolactin concentrations, not observed during the
control infusions.
King et al [68] reported that trailer transport for 30 mi-
nutes and stall confinement for 60 minutes, both consid-
ered forms of stress in horses, did indeed increase plasma
prolactin concentrations in mares in winter. In the second
phase of that experiment, half the mares were fed a fish oil
supplement for 40 days that provided 22 g docosahexae-
noic acid and 18.5 g of eicosapentaenoic acid per day.
Interestingly, fish oil feeding reduced the cortisol response
to the two stressors, whereas it increased the prolactin
responses.
3.4. Feeding Effects
Depew et al [69] were the first to describe the rise in
plasma prolactin concentrations following a combined
 D.L. Thompson Jr., E.L. Oberhaus / Journal of Equine Veterinary Science 35 (2015) 343–353
pelleted feed and hay meal at noon after an overnight
period of feed deprivation. Prolactin concentrations grad-
ually increased from the time of feeding and peaked about
1 to 2 hours later. The rise was greater in stallions than in
mares, and there was no change in prolactin concentrations
in unfed animals. Subsequently, Depew et al [70] assessed
the prolactin responses to gastric infusion of water alone, or
equivalent volumes of saline, egg albumin, or corn starch
solutions, to the consumption of a pelleted feed meal. Only
the consumption of the pelleted feed meal resulted in a rise
in plasma prolactin concentrations, indicating that the
presence in the stomach of any of the basic components of
the feed alone was not the stimulus for prolactin secretion.
Nadal et al [71] later compared several feedstuffs as the
meal in a similar experiment and found that the full
amount of pelleted feed, one-fourth the amount of pelleted
feed, pelleted feed plus water, corn, and alfalfa cubes all
produced similar prolactin rises, in spite of the fact that the
amount of alfalfa cubes consumed was low and the insulin
response was correspondingly minimal.
Thompson et al [21] suggested that the consistent 50%
drop in prolactin concentrations in 12 mares brought in
from pasture in the morning for blood sampling over the
next 8 hours might have been due to the switch from ad
libitum grazing to total feed restriction for that period of
time. Moreover, mares restricted to 50% of their energy
requirements for 27 days had no rise in prolactin concen-
trations in response to a pelleted feed meal [72], whereas
there was a tendency for a rise in mares previously fed
100% of their energy requirements daily. However, the
effect of reduced feed intake or lack thereof on prolactin
secretion was directly tested by a second experiment
described by Nadal et al [71], which revealed that total feed
deprivation of mares for 72 hours did not alter prolactin
concentrations in daily blood samples. Similarly, a feeding
regimen of dried grass hay in a dry lot [73] did not alter
prolactin concentrations in mares compared with when
they were on pasture 24 hours per day (ad libitum grazing).
For comparison, the dried hay-dry lot regimen reduced
average insulin, leptin, and IGF-I concentrations dramati-
cally compared with when mares were on ad libitum
pasture.
Sticker et al [74] studied the direct IV infusion of free
amino acid solutions (neutral pH) on prolactin concentra-
tions in stallions, geldings, and mares. Arginine, infused at
2.855 mmoL/kg of body weight in 1 L of water, produced
the greatest response in plasma prolactin concentrations,
and lysine and glutamic acid at the same doses produced
similar but smaller prolactin responses. Aspartic acid and
1 mg of N-methyl-D,L-aspartate/kg of body weight were
without effect.
3.5. Estrogen Effects
Roser et al [19] first described an association between
plasma estradiol concentrations on day 3 of the estrous
cycle and subsequent rises in prolactin concentrations in
cyclic mares. The estradiol peak preceded the prolactin
peak by 1.5 to 2 hours. Subsequently, Thompson et al [75]
described the direct effect of estradiol administration on
prolactin concentrations in plasma and in the pituitary of
347
ovariectomized pony mares treated daily for 21 days with
estradiol-17b in vegetable shortening. Although plasma
prolactin concentrations in daily blood samples were only
transiently increased by about 35% in the first 5 days of
treatment, prolactin content in the pituitary gland was
increased to approximately 3.5 mg relative to that in con-
trol ponies of approximately 0.7 mg. This accumulation of
prolactin in the pituitary combined with the maintenance
of normal or slightly higher plasma concentrations implied
an increase in production of prolactin induced by estradiol.
It was this fact that served as the basis of the hypothesis of
Kelley et al [49] that pretreatment with estradiol might
enhance the prolactin response to dopaminergic antago-
nists in seasonally anovulatory mares in winter. In fact,
every-other-day injection of estradiol benzoate to mares in
January greatly enhanced the prolactin response to daily
injections of sulpiride started 10 days later, compared with
sulpiride injections alone (up to 17 ng/mL vs. 3 ng/mL,
respectively, in daily samples).
As a follow-up to Kelley et al [49], Thompson et al [76]
compared the use of a single injection of estradiol benzo-
ate (300 mg) in biodegradable microspheres and a single
injection of estradiol cypionate (ECP; 100 mg) as possible
alternatives to the every-other-day estradiol benzoate
injections in oil (11 mg/injection) used previously. Plasma
estradiol concentrations produced by the ECP injection
were very similar to those of the every-other-day estradiol
benzoate injections and were therefore chosen for future
studies in seasonally anovulatory mares (detailed below).
How estradiol stimulates prolactin production by the
equine pituitary was a question raised by Clavier et al [77].
Prolactin responses to increasing doses of sulpiride in
vehicle-treated geldings and in geldings treated with
100 mg of ECP were used to generate dose-response curves
from which the effective dose-50 (dose at which 50% of
maximal response is achieved) could be derived. The
conclusion was that estradiol greatly enhances prolactin
secretion in response to sulpiride, but the sensitivity of the
prolactin-secreting cells to sulpiride is not altered.
It should be noted that the estradiol enhancement of
prolactin secretion in response to sulpiride is dependent on
both components (estradiol and sulpiride), and the absence
or withdrawal of either results in the absence or waning of
the effect. This was observed in the data of Kelley et al [49],
in which prolactin concentrations dropped from 17 to
5 ng/mL within 4 days after the cessation of estradiol
benzoate injections. In addition, the mares in that experi-
ment not receiving estradiol did receive daily sulpiride
injections but had minimal change in prolactin secretion
relative to pretreatment. Given this obvious synergy
between estrogen and antidopaminergic activity, Thomp-
son et al [43] asked whether a different known secreta-
gogue of prolactin, TRH, could replace sulpiride with the
same effects on prolactin secretion after ECP administra-
tion. Treatment of geldings with vehicle or 100 mg ECP
10 days before daily TRH injections did not enhance pro-
lactin secretion in the ECP-treated group as would have
been expected if sulpiride had been administered. In that
same report [43], other stimuli of prolactin secretion (ex-
ercise and PGF2a) produced equivalent prolactin responses
in vehicle-treated and ECP-treated geldings, whereas
348 D.L. Thompson Jr., E.L. Oberhaus / Journal of Equine Veterinary Science 35 (2015) 343–353
sulpiride injection revealed the greater response in
ECP-treated geldings. Thus, the synergism between estro-
gen and sulpiride on prolactin secretion is unique for the
antidopaminergic agents.
Given these known effects of estrogen on prolactin
secretion, combined with the description of endogenous
pulses in mares around the time of luteolysis (discussed
above), it may seem odd that Becker and Johnson [29] did
not detect any change in prolactin concentrations across
the estrous cycle of mares. Likely, daily samples were not
frequent enough to detect the endogenous pulses around
luteolysis. Secondly, as mentioned for mares treated with
estradiol in Thompson et al [75], estrogen changes may not
be reflected in an increase in secretion per se (in the
absence of an antidopaminergic agent). However, Hebert
et al [78], using every-other-day injections of a small dose
of sulpiride, looked for possible variations in prolactin
response across the estrous cycle of six mares but found no
change relative to the follicular phase, early diestrus, or late
diestrus. It is possible that the concentrations of estradiol
produced in estrous mares may not be high enough to
synergize with sulpiride. Alternatively, a potential stimu-
latory effect of estradiol from the ovaries during estrus may
in fact persevere throughout the entire estrous cycle.
3.6. Opioid Involvement
The possible involvement of endogenous opioids in the
regulation of prolactin secretion has been studied almost
exclusively by Dr Christine Aurich et al in Austria. In 1997
[79], they reported that naloxone, an opioid antagonist
agent, stimulated prolactin secretion in mares that had
previously been administered melatonin but not in mares
that had received estradiol or melatonin plus estradiol.
Naloxone administration to otherwise untreated mares in
the breeding and nonbreeding season had no effect on
prolactin secretion [80]. In contrast, there was a prolactin
response to naloxone in pregnant mares at and beyond
226 days of gestation, and the responses increased as
gestation advanced. In stallions, naloxone injection did
not alter prolactin concentrations when administered in
December, March, or June [81].
4. Known Biological Effects
The role of prolactin in physiological processes in the
horse has been far less defined than for other species. Three
main areas of action have been described: (1) the impor-
tance of prolactin in mammary development and lactation
at parturition and the impact of fescue associated endo-
phyte ergot alkaloids; (2) hair shedding in the spring and
hair growth in fall; and (3) prolactin’s role in the recru-
descence of mares’ ovaries in the spring transition from
inactivity to full activity.
4.1. Mammary Growth and Lactation
The role of prolactin in mammary growth and lactation
in horses has been indirectly confirmed from the sup-
pressive effects of consumption of tall fescue grass infected
with the endophyte Neotyphodium coenophialum (formerly
Acremonium coenophialum). Cross et al [59] summarized
the literature of that time and suggested that the ergot
alkaloids produced by the endophyte mimic the activity of
dopamine in the body, one effect being a reduction in
prolactin secretion [60,61]. As mentioned earlier, Ireland
et al [51] reproduced many of the symptoms of fescue
toxicosis in pregnant mares with injections of bromocrip-
tine. Simultaneous treatment of mares with perphenazine
(a dopaminergic antagonist) in that experiment prevented
the bromocriptine effects, including those on prolactin
concentrations. Similarly, Cross et al [59] emphasized that
the detrimental effects in gravid mares of fescue grazing
can be avoided by daily treatment (feeding) of domper-
idone. A commercial product, Equidone, is now sold for that
purpose through veterinary prescription.
Separating the effects of the ergot alkaloids per se from
the effects of reduced prolactin secretion has not been
possible due to the lack of large amounts of equine pro-
lactin that could be used to treat horses. McDowell et al
[62], for example, have shown the vasoconstrictive effects
of fescue ingestion on the blood flow through the distal
palmar artery of the foreleg of the horse, a tissue that would
not intuitively be associated with prolactin. Other effects,
such as heat intolerance [60], may be due to direct activity
of the ergot alkaloids on the hypothalamus.
Given successful research on the induction of lactation
in other species, prolactin was suspected to be a major
factor in attempts to induce lactation in nonpregnant mares
for potential nurse mares. Daels et al [82] published an
excellent review in 2002 of the literature leading up to their
recommended protocol for inducing lactation in nonpreg-
nant mares. The procedure, derived primarily from the
research results of Chavatte-Palmer et al [83] and Guil-
laume et al [84], involves treatment of mares with intra-
vaginal sponges containing altrenogest (a progestogen
compound) and estradiol benzoate for 7 days and subse-
quently with sulpiride and a second sponge of steroids on
day 8. With few other modifications, this protocol was
highly successful for inducing lactation, which continued
without further hormonal treatment, and was able to
support foal growth up through weaning.
Interestingly, perturbations in mammary growth (e.g.,
idiopathic agalactia [85]) have been reported with no
apparent perturbation in plasma prolactin concentrations.
Similarly, our Endocrine Laboratory in the School of Animal
Sciences at Louisiana State University has been asked to
analyze plasma samples over the years for prolactin from
mares having unexplained mammary growth and apparent
lactation. In no case, out of about 10, has hyperpro-
lactinemia been found. This is not to say that normal,
unstimulated prolactin concentrations might not be suffi-
cient for other factors to cause onset of lactation; however,
the vast majority of normal, nonpregnant mares do not
lactate, even in the summer when prolactin concentrations
are the highest.
4.2. Hair Shedding and Fall Hair Growth
Burkhardt [86] was the first to describe the use of indoor
lighting to stimulate the ovaries of seasonally anovulatory
pony mares during the winter. He mentioned in that report
 D.L. Thompson Jr., E.L. Oberhaus / Journal of Equine Veterinary Science 35 (2015) 343–353
that the lighted mares actually began to shed their winter
coat, although the outdoor temperatures they were
exposed to during the day were very cold. Kooistra and
Ginther [87] carefully studied the coat shedding of mares
exposed to 16 hours of light per day starting in November
compared with control (unlighted) mares and found a
35-day hastening of the shedding of hair in the lighted
mares. Thus, it was not surprising, given a similar increase
in prolactin secretion produced by the same lighting
pattern in mares described by Johnson [34], that daily
treatment of seasonally anovulatory pony mares with
recombinant porcine prolactin starting January 15 induced
hair shedding within 14 days [88]. Because the recombi-
nant porcine prolactin resulted in antibody production
against it within 28 days, the amount of hair shed peaked at
28 days and declined rapidly thereafter. Apparently, the
antibodies against the injected prolactin crossreacted with
the ponies’ own prolactin because 3 months after cessation
of treatment (May), the treated ponies still had large
patches of retained winter coat on their sides and un-
derbellies, whereas the control ponies had shed completely
to a smooth summer coat.
Donadeu and Thompson [89] reported a similar stimu-
lation of hair shedding associated with increased prolac-
tin concentrations in mares administered sulpiride from
January 15 to February 15. During the autumnal transition
period, suppression of prolactin secretion in mares
with every-10-day injections of cabergoline [55] from
September to November initially caused an approximate
25% increase in hair shaved from the shoulder in the first
30 days. However, because of the naturally rising increase
in hair growth of the control mares and an apparent
plateau of hair growth in the cabergoline-treated mares,
the effect was reversed after 61 days of treatment. In a
similar experiment, mares treated with cabergoline during
later winter and early spring had an obvious delay in
shedding of their winter coats when compared with con-
trol mares [53]. Some mares retained a winter coat well
past the waning effects of cabergoline treatment.
4.3. Induction of Ovarian Activity and Ovulation in Winter
Nequin et al [90] were the first to demonstrate that the
rise in plasma prolactin concentrations in the spring likely
had a role in the recrudescence of the equine ovaries at that
time. They treated mares in January with a single dose of
200 mg of ovine prolactin. Relative to control mares, the
treated mares grew larger follicles, up to 54 mm in one
mare, within a few weeks. Although most of the induced
large follicles regressed, one mare went on to ovulate a
60-mm follicle 9 weeks after treatment. Oddly, no treated
mares exhibited estrus in conjunction with the induced
follicular activity. In the same report, Nequin et al [90]
described the use of fluphenazine, a dopaminergic antag-
onist, to stimulate prolactin secretion in mares starting in
January. The rise in prolactin concentrations reported was
minimal; however, treated mares displayed first estrous
behavior 4 to 5 weeks earlier than controls and grew a
25-mm follicle 6 to 7 weeks earlier than controls. In
contrast, all mares ovulated around the same time (at 13 to
14 weeks).
349
In 1997, Besognet et al [91] reported that sulpiride could
be used to stimulate the ovaries of mares when treatment
started on February 5. The average time to ovulation,
although shorter than for control mares (74 days), was still
41 days (around March 18). In a subsequent report, Daels
et al [92] concluded that the success of sulpiride treatment
for inducing ovulation in seasonally anovulatory mares
housed outdoors was minimal, whereas previous light-
ing (extended photoperiod) and indoor housing greatly
improved success. These latter results were similar to those
reported by Donadeu and Thompson [89], in which daily
treatment of seasonally anovulatory mares from January 14
to February 14 with sulpiride did not stimulate ovarian size
or activity, although prolactin concentrations were
increased and hair shedding was stimulated relative to
control mares. Panzani et al [93] treated mares with sul-
piride for 21 days when the first follicle of 25 mm or larger
was attained (transitional mares) and reported that treat-
ment hastened first ovulation by 25 days (median of
18 days for treated mares and 43 for controls).
Brendemuehl and Cross [94] first reported on the use of
domperidone, an orally active dopamine antagonist, on
prolactin secretion and ovarian activity in seasonally
anovulatory mares. They started mares on oral domper-
idone on January 15, and the average time to ovulation
thereafter was 27 days. This was an advancement in time of
78 days relative to control mares. Six of the eight treated
mares continued to cycle after the first ovulation and two
returned to inactivity for an average of 67 days after
ovulation. Plasma prolactin concentrations in the treated
mares were dramatically increased, averaging 25.5 ng/mL
after feeding on day 7, relative to 2.5 ng/mL in control
mares, and likely contributed to the rapid ovarian
responses.
Somewhat contrary to the excellent results of Brende-
muehl and Cross [94] with domperidone feeding, Mari et al
[95] compared daily domperidone feeding and sulpiride
injection directly in the same trial for inducing ovulation in
mares started on treatment on February 15. Sulpiride
treatment in that case was superior to domperidone
feeding, inducing ovulation in an average of 39 days com-
pared with domperidone at 75 days.
Brendemuehl and Cross [94] noted in their 2000 pub-
lication: “The significant increases in follicular develop-
ment and concentrations of estrogen conjugates that were
observed to occur without concurrent increases in FSH
concentration indicate that either domperidone or prolac-
tin may have a direct effect on the ovary.” The question of
whether dopaminergic antagonists act via their stimulation
of prolactin or perhaps directly on the ovaries cannot be
answered from experiments with sulpiride, domperidone,
or other antagonists. However, similar to the experiment
Nequin et al [90] conducted with a single injection of ovine
prolactin, Thompson et al [88] treated seasonally anovu-
latory pony mares daily with recombinant porcine prolac-
tin (4 mg) beginning January 15. The time to first ovulation
(assessed by first high progesterone concentration in
jugular plasma) in the treated mares was 21 days from the
start of treatment. Control mares ovulated an average of
36 days later than the treated mares. Thus, in the absence of
exogenous dopaminergic antagonists, prolactin alone can
350 D.L. Thompson Jr., E.L. Oberhaus / Journal of Equine Veterinary Science 35 (2015) 343–353
stimulate ovulation in mares in winter that otherwise
would not ovulate for another month or more. Although
not totally excluding the possibility that dopamine antag-
onists might affect the ovaries directly, these results
strongly support the model in which naturally rising pro-
lactin concentrations in the spring somehow contribute to
the growth of ovarian follicles at that time, leading to the
first ovulation of the season. A recent report by Oberhaus
et al [96] describing prolactin receptors in the equine ovary
supports the hypothesis that prolactin may affect the ovary
directly during the spring transition from quiescence to full
activity. Although receptors for dopamine have also been
described in the equine ovary as well [97], the direct effect
of prolactin itself on ovarian activity [88,90] would seem to
support prolactin as the intermediary in the effects of
antidopaminergic agents.
Given that there is no bulk source of equine prolactin
available to date and because recombinant porcine pro-
lactin treatment of pony mares eventually caused antibody
production [88], research into the use of dopaminergic
antagonists has continued with the quest of maximizing
positive responses (ovulations) with a minimum of effort
(few injections or treatments). Applying the basic knowl-
edge derived from Thompson et al [75] regarding the
estradiol effects on prolactin production and secretion,
Kelley et al [49] pretreated seasonally anovulatory mares
starting on January 11 with every-other-day injections of
11 mg of estradiol benzoate. Those injections continued for
a total of 10 injections; control mares received oil in-
jections. On day 11, mares in both groups, treated and
control, were started on daily sulpiride (250 mg) injections
in vegetable shortening, which were continued for 45 days.
Estradiol pretreatment enhanced the prolactin response to
sulpiride from an average of 1 to 2 ng/mL in control mares
to a peak of 16 ng/mL by 6 days after start of sulpiride.
Plasma prolactin concentrations remained elevated at
5 ng/mL at 24 days after start of sulpiride. In response,
estradiol-treated mares ovulated within an average of
29 days (corresponding to February 9) compared with
74 days in mares receiving sulpiride only. An additional
effect of the estradiol pretreatment was a consistent rise in
plasma luteinizing hormone (LH) concentrations, similar to
that reported by Garcia and Ginther [98] in ovariectomized
pony mares in winter, which rose from <1 ng/mL to a peak
of 4.5 ng/mL over the first 20 days of estradiol exposure
(controls remained <1 ng/mL throughout). Such a rise in LH
concentrations has not been observed in mares receiving
dopaminergic antagonist alone and very likely contributed
to the positive ovarian response.
In that same report, Kelley et al [49] described a second
experiment in which a single injection of domperidone in
microparticles of a biodegradable polymer was injected in
lieu of daily sulpiride injections. Pretreatment with estra-
diol benzoate, as in the first experiment, followed by the
injection of domperidone, stimulated greater prolactin
release than domperidone injection alone. With the goal of
eventually reducing the protocol down to one or two
injections only, Thompson et al [76] compared every-
other-day estradiol benzoate injections to single in-
jections of estradiol in biodegradable microparticles or
ECP. As mentioned earlier, plasma estradiol concentrations
produced by 100 mg of ECP were very similar to those
produced by the estradiol benzoate injections. Based on the
results with domperidone and ECP, several trials were
conducted in Louisiana and Kentucky with various com-
binations and timings of the two compounds, and those
results were summarized by Mitcham et al [99]. In general,
positive responses (defined as ovulation in 35 days or less)
were observed for most combinations (43% to 50% in
two cases, up to 71% in one case); however, no simplified
protocol tested was able to duplicate the success of Kelley
et al [49].
When domperidone was approved for commercial sale
as a treatment for fescue toxicity in mares, there was a shift
from it back to sulpiride as the dopaminergic antagonist of
choice for the ovarian inducement protocols. Mitcham
[100] compared the use of 0.75 or 1.5 g of sulpiride in a
slow-release oily vehicle injected on days 1, 6, and 11 after a
single injection of 100 mg of ECP to a single injection of
1.5 g of domperidone in biodegradable microparticles.
Plasma prolactin responses to sulpiride were greatest for
the 1.5 g injections and peak prolactin concentrations
averaged 24, 44, and 60 ng/mL on days 2, 7, and 12. For
comparison, the domperidone produced prolactin con-
centrations in the range of 6 to 9 ng/mL through 22 days of
treatment. Although a pretreatment with thyroxin was
included as a factor across all groups, it had no influence of
prolactin secretion or success rate (ovulation within
32 days). Success rate for the ECP plus 1.5 g sulpiride in-
jections averaged 77% and was greater than all other
treatments and the control group, each of which averaged
25% or less. As in previous trials, ECP injection resulted in a
gradual rise in LH concentrations up to a plateau of 4 to
5 ng/mL at 10 to 20 days after injection.
Since the last experiment by Mitcham [100] was
completed, attention at the LSU AgCenter Horse Farm has
been focused on alternative vehicles for sulpiride with the
goal being a reduction down to one, or at most two, in-
jections in the ECP-sulpiride protocol. Recently, it was
found that a single subcutaneous injection of 3 g of sul-
piride in vegetable shortening (which stays semisolid at
body temperature) in the lower girth area of ECP-treated
geldings produced plasma prolactin concentrations of 18
to 28 ng/mL for at least 7 days after injection. This approach
is currently being tested in seasonally anovulatory mares
in combination with 50 mg of ECP and thus far shows
promising results.
Retrospective analysis of the various experiments con-
ducted at the LSU AgCenter Horse Farm attempted to
answer the question of why some mares respond to the
ECP-dopamine antagonist treatment while other mares do
not. The individual mares’ responses of prolactin and LH, as
well as their characteristics such as body condition, age,
farm location, and depth of anestrus, were considered. The
only trend in the data overall was that mares that had
robust responses in both prolactin and LH were the most
likely to respond with ovarian activity and ovulation. Mares
with no LH response rarely had ovarian responses, whereas
there were times when a mare would have a robust pro-
lactin response and good LH response but no ovarian
response. This analysis was limited in that there were no
mares in the analyses with poor body condition (e.g., four
 D.L. Thompson Jr., E.L. Oberhaus / Journal of Equine Veterinary Science 35 (2015) 343–353
or below), and it is suspected that such a lean condition
would likely preclude an ovarian response.
5. Conclusions
After 39 years of research on equine prolactin, much is
known about factors affecting its secretion, whereas its
effects on physiologic functions are far less understood.
Questions such as prolactin’s role in behavior, the mecha-
nism by which it is released during stress, how it affects the
mare’s ovary in spring, and why it is released after a meal
all deserve further research. The application of the basic
knowledge on prolactin secretion and effects in the horse
generated to date in the areas of fescue toxicosis, induction
of lactation, and stimulation of seasonally anovulatory
mares provides an excellent example of how the gradual
accumulation of knowledge derived from basic research
questions can generate applied solutions to real-world
problems.
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