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Follicle Wave Growth in Cattle

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Reprod Dom Anim 37, 191–200 (2002)
Ó 2002 Blackwell Verlag, Berlin
ISSN 0936-6768

Follicle Wave Growth in Cattle

M Mihm1, MA Crowe2, PG Knight3 and EJ Austin2
1
University of Glasgow Veterinary School, Glasgow, UK; 2Faculty of Veterinary Medicine and the Conway Institute, University College Dublin,
Dublin, Ireland; 3School of Animal and Microbial Sciences, University of Reading, UK

Contents (Adams et al. 1992a; Sunderland et al. 1994; Ginther

Ovarian follicle growth in cattle culminates in the selection of a et al. 1997). During declining FSH and over the
single dominant follicle which attains the ability for final following 2–3 days fewer and fewer follicles from the
maturation and ovulation once or twice during the luteal phase original cohort continue growing until only one single
and at the end of the oestrous cycle, as well as during other follicle (the dominant follicle, DF) is selected while the
reproductive states. This review will describe in detail the first remaining cohort members become static and undergo
follicle wave of the cycle leading to selection of the first wave atresia via apoptosis (subordinate follicles; Austin et al.
dominant follicle, indicating the specific gonadotrophin de-
2001). The freshly selected DF demonstrates enhanced
pendencies of cohort and dominant follicles, and relating
follicle fate to steroidogenesis. As a differential gonadotrophin growth and steroidogenesis, specifically increased oes-
response of growing antral follicles during the follies-stimula- tradiol secretion before FSH even reaches nadir con-
ting hormone (FSH) decline may determine which follicle centrations (Ginther et al. 1997; Austin et al. 2001).
becomes selected, first wave follicles are also characterized in Following its selection, the DF grows to a much larger
relation to intrafollicular growth factors, which may modify size than all other ovarian follicles (from ca. 8.5 mm at
the gonadotrophin response, such as inhibins and members of the end of selection to 12–20 mm), is responsible for the
the insulin-like growth factor (IGF) family. Subsequently, the high ovarian oestradiol secretion and maintains low
follicular control of the transient FSH rise and decline so FSH concentrations to prevent any other cohort growth
crucial to dominant follicle selection will be discussed. It is (Ireland et al. 1984; Ginther et al. 1999, 2000a,b).
concluded that successful hormonal manipulation of follicle
Continued growth and oestradiol synthesis of the first
wave growth and dominant follicle selection will depend on
our detailed understanding of the gonadotrophin requirements DF of the cycle does not usually occur for more than
of differentiating wave follicles. 3–4 days, as the developing corpus luteum with its
progesterone secretion negatively regulates the LH pulse
pattern and the LH-dependent DF also becomes atretic
Introduction (Fig. 2; Sunderland et al. 1994; Evans et al. 1997). The
In cattle, growth of ovarian antral follicles from initial decline in oestradiol secretion on day 6 is followed
approximately 300 lm in diameter to a size of 3–5 mm by stasis and loss of dominance between days 7 and 9,
which can be detected by transrectal ultrasound scan- causing another transient FSH rise, wave emergence and
ning is calculated to take more than 30 days (Lussier selection of a new DF while the old DF regresses
et al. 1987). Such early antral growth is considered to be (Sunderland et al. 1994). If luteolysis occurs during the
gonadotrophin independent (Scaramuzzi et al. 1993).
Subsequent growth is rapid and occurs in a wave-like
fashion with growth rates of up to 2 mm/day detected in
larger antral follicles. Follicle wave growth in cattle is
acutely gonadotrophin, specifically follicle-stimulating
hormone (FSH)-dependent, and the almost simulta-
neous emergence of a cohort of small (3–5 mm) follicles
detected by ultrasound is always associated with tran-
sient FSH rises (Fig. 1; Adams et al. 1992a; Sunderland
et al. 1994). This review will explore the pituitary –
ovarian interactions in relation to changing FSH con-
centrations and follicle wave growth, in an attempt to
elucidate the regulatory mechanisms involved in limiting
the number of the species-specific ovulatory quota to
one in cattle.

Gonadotrophin dependency of follicle waves

Description of follicle wave growth (Figs. 1 and 2)
Following the gonadotrophin surge and almost coinci-
dent with ovulation a ‘secondary’ or ‘peri-ovulatory’
transient FSH rise occurs which stimulates up to 24
small antral follicles (the cohort) to grow beyond 4 mm
in diameter (emergence; days 1–2 of the oestrous cycle)
Fig. 1. Schematic diagram of the transient FSH rise and growth of the
first follicle wave of the oestrous cycle in cattle; following selection the
fate of the dominant follicle (DF) depends on the prevalent LH pulse
pattern; in an environment characterized by frequent LH pulses the
DF undergoes final maturation and induces the gonadotrophin surge,
while the DF becomes atretic when LH pulses are infrequent.
DF: dominant follicle; SF: subordinate follicles

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192
Fig. 2. Schematic diagram of the hormone environment and dominant
follicle turnover in heifers with three dominant follicles per cycle (see
text); shaded follicles indicate onset of atresia
dominance period of the second DF, then it will ovulate
(Cooke et al. 1997a), however, if the corpus luteum is
still active suppressing LH pulse frequency, then the
second DF will also undergo atresia, and a third wave
emerges giving rise to the third DF. Following regres-
sion of the corpus luteum, a frequent LH pulse pattern
during the follicular phase supports the second or third
DF which can now undergo final differentiation, induce
the gonadotrophin surge, ovulate and luteinize. Antral
follicle waves preceded by transient FSH rises and
leading to DF selection are seen in all reproductive
states in cattle, i.e. during the oestrous cycle (Adams
et al. 1992a; Cooke et al. 1997a), pregnancy (Ginther
et al. 1989), before puberty (Evans et al. 1994), and
during postpartum (Stagg et al. 1998) or nutritional
anoestrus (Rhodes et al. 1995).
Steroidogenesis during the first follicle wave
Growing cohort and dominant follicles are histologically
healthy and show an oestradiol to progesterone ratio
of > 1 in follicular fluid (oestrogen-active); when follicles
undergo atresia determined histologically, oestradiol
synthesis ceases and intrafollicular progesterone
concentrations may increase as occurs in subordinate
follicles following DF selection or in the DF after loss of
dominance (Ireland and Roche 1983; Badinga et al. 1992;
Sunderland et al. 1994). Thus, the ability to synthesize
high amounts of oestradiol is an indicator of follicle
‘success’ and usually related to progress within the
follicle wave. For example, intrafollicular oestradiol
concentrations increase rapidly in the largest cohort
follicles during the first 33 h of the FSH decline following
its transient rise (Austin et al. 2001). Within 24 h and
before FSH reaches nadir concentrations, the largest size
and highest intrafollicular oestradiol concentrations are
already linked in the most successful cohort follicle,
while the oestrogen-activity of other cohort members,
the future subordinate follicles, is already decreased
compared with the DF (Mihm et al. 1997; Austin et al.
2001). Underlying the high oestrogen activity of the
freshly selected DF are enhanced expression of the genes
for aromatase, 3b-hydroxy-steroid dehydrogenase and
FSH-receptor, and the acquisition of LH receptors in
granulosa cells (Ireland and Roche, 1983; Xu et al. 1995;
Bao et al. 1997a,b; Evans and Fortune 1997).
M Mihm, MA Crowe, PG Knight and EJ Austin
Interestingly and despite divergence in oestradiol
synthesis and size, the percentage of apoptotic granulosa
cells did not differ between the freshly selected DF and
its largest subordinate follicle (Austin et al. 2001).
Following its selection the first DF ceases to produce
high amounts of oestradiol between days 5 and 8 of the
cycle despite continued growth; once loss of dominance
is confirmed by the emergence of the second follicle
wave, old DFs have become oestrogen-inactive (Ireland
and Roche 1983; Badinga et al. 1992; Sunderland et al.
1994).
Inhibins and insulin-like growth factor (IGF) binding
proteins during the first follicle wave (Fig. 3)
During the first 33 h of the FSH decline following its
transient rise, the emerging cohort already splits into
two distinct groups: the successful rapidly growing
largest follicles and the smaller cohort follicles which
are unable to maintain the same growth rates and
oestradiol synthesizing capacity. Such differential
response to the same FSH environment may be funda-
mental to DF selection and thus intrafollicular actions
of FSH-induced ovarian growth factors which in turn
modulate cohort follicle response to the gonadotrophins
may be essential to follicular success. Changes in
intrafollicular amounts of proteins belonging to the
inhibin and IGF family during progression of the first
follicle wave have, therefore, been determined and may
be useful as predictive markers for follicle fate during
declining FSH (Mihm et al. 2000a).
Inhibins exert an FSH-suppressive action on the
pituitary and exist in various dimeric (biologically
active) (a and b subunits) molecular weight (MW) forms
in bovine follicular fluid (Good et al. 1995); monomeric
inhibin a subunit forms are also very abundant in
follicular fluid and may negatively influence follicular
FSH response (Schneyer et al. 1991) thus justifying
current research efforts into their functions within the
follicle and on the oocyte (Silva et al. 1999). Activin is a
dimer linking two b inhibin subunits and its receptor
interactions are regulated by levels of follistatin, which
Fig. 3. Schematic diagram of the proposed actions of intrafollicular
peptides belonging to the insulin-like growth factor system following
selection of dominant follicles in cattle (see text)
Follicle Wave Growth in Cattle
neutralizes activin functions in pituitary and ovary
(Robertson et al. 1987; Findlay 1993). Important
intrafollicular actions are proposed both for inhibin
and activin in growth, steroidogenesis and FSH receptor
acquisition (LaPolt et al. 1989; Xiao et al. 1992; Knight
and Glister 2001) and characteristic changes during
cohort follicle growth may convey an advantage to the
future DF. During the first 33 h of the FSH decline, an
increase in the higher MW inhibins is seen in the fastest
growing cohort follicles concomitant with the increase in
intrafollicular oestradiol; free activin concentrations are
increased in the largest follicle of the first follicle wave
(Austin et al. 2001). In the next 24 h high amounts of
higher MW inhibins are similarly maintained in the two
largest follicles belonging to the first follicle wave despite
differences in size and intrafollicular oestradiol. In
addition, the largest follicle shows a further reduction
in follistatin concentrations (Austin et al. 2001). Only
24 h later the DF alone maintains high amounts of
higher MW inhibins while its subordinate follicles have
low intrafollicular amounts of the higher MW inhibins,
and increased amounts of the smallest (34 kDa) inhibin
dimer and follistatin compared with the DF (Mihm et al.
1997; Austin et al. 2001). Following its loss of domin-
ance, the first-wave DF also shows low amounts of the
higher MW inhibins and increased amounts of the
34 kDa inhibin dimer and this is associated with much
reduced intrafollicular oestradiol and aromatase activity
(Badinga et al. 1992; Sunderland et al. 1996). Thus, a
clear pattern during growth of the first follicle wave
emerges: successful follicles are able to respond to the
transient FSH rise with enhanced growth and oestradiol
synthesis, as well as increased production of the higher
MW inhibins and activin, while follistatin and amounts
of the native 34 kDa inhibin dimer are kept at low
concentrations. Despite enhanced inhibin synthesis dif-
ferentiating successful from less successful cohort mem-
bers, it does not distinguish between the two closest
competitors for dominance until after DF selection and
stasis of the largest subordinate follicle has occurred
(Mihm et al. 2000a; Austin et al. 2001).
Members of the IGF system which have been char-
acterized in bovine follicles are the two peptides IGF-I
and II, the IGF-type 1 receptor, four different and
specific IGF binding proteins (IGFBPs), which prevent
IGF receptor interaction by binding their ligand with
high affinity, and very recently a specific IGFBP4
protease, pregnancy-associated plasma protein A
(Spicer and Echternkamp 1995; Rivera et al. 2001;
Mazerbourg et al. 2001). Free (unbound) IGFs stimulate
proliferation of follicular granulosa cells, and enhance
oestradiol, inhibin and activin synthesis in vitro, with
effects depending on FSH concentrations (Glister et al.
2001). Follicle oestrogen activity is negatively correlated
with intrafollicular amounts of the IGFBPs < 40 kDa
(that is IGFBP2, 4 and 5) (Echternkamp et al. 1994),
and increases in the lower MW IGFBP2, 4 and 5 have
been seen in atretic bovine follicles (Mazerbourg et al.
2000). During the first 53 h of the FSH decline amounts
of the lower MW IGFBPs are maintained similarly low
in the three fastest growing follicles of the cohort despite
FSH declining more than 50% and despite differences
appearing in size and intrafollicular oestradiol (Austin
193
et al. 2001). The less successful smaller follicles of the
cohort already show increased intrafollicular IGFBP4
and 5 in the first 33 h of the FSH decline. Once the DF
has been selected, IGFBPs are maintained at low levels
(IGFBP4, 5) or are even reduced further (IGFBP3, 2)
and the DF demonstrates enhanced IGF bioavailability
as a result of higher IGF-II synthesis and increased
binding of IGF-I, while amounts of IGFBP4 and 5 are
increased in subordinate follicles after DF selection
compared with cohort follicles before selection (de la
Sota et al. 1996; Stewart et al. 1996; Mihm et al. 1997;
Austin et al. 2001). Atresia of subordinate follicles also
appears to be associated with increased expression of the
IGFBP2 gene (Yuan et al. 1998). When the two closest
competitors for dominance were examined before mor-
phological selection occurred, the cohort follicle which
became the DF already had lowest amounts of IGFBP4
(Mihm et al. 2000a); thus reduced IGFBP4 and high
levels of bioactive IGFs are considered essential for DF
selection enabling the DF to survive declining and nadir
FSH concentrations without undergoing apoptosis. Two
questions remain, however, and need to be solved for
future manipulation of the IGF axis and thus follicle
wave growth and differentiation: first, are there specific
functions attached to different IGF binding proteins?
Maintaining low IGFBP4 while having relatively abun-
dant IGFBP3 still appears to limit bioavailability of
locally available IGFs. Secondly, are concentrations
of specific IGF binding proteins regulated at the level of
gene expression or is binding activity controlled via
proteolytic cleavage in follicular compartments? This
question appears particularly significant at the moment,
as specific IGFBP proteases have recently been des-
cribed in ruminants (Besnard et al. 1996; Mazerbourg
et al. 2000) and the DF appears to have more of the
specific IGFBP4 protease than its subordinate follicles
(Chandrasakher et al. 1996). The IGFBP4 protease is
most likely plasma-associated pregnancy protein-A
(PAPP-A). This is synthesized by bovine granulosa cells
and cleavage of IGFBP4 is dependent on the presence of
IGF and can be influenced by other IGFBPs and
components of the extracellular matrix (Lawrence et al.
1999; Mazerbourg et al. 2000, 2001). Expression of the
PAPP-A gene is related to aromatase and LH receptor
gene expression in granulosa cells and thus may be
important for the final stages of DF selection
(Mazerbourg et al. 2001).
During its subsequent growth phase the first DF
maintains low amounts of the lower MW IGFBPs, while
loss of dominance of the first DF is accompanied by
increases in the lower MW forms of IGFBPs and
increased incidence of granulosa cell apoptosis (de la
Sota et al. 1996; Stewart et al. 1996; Manikkam and
Rajamahendran 1997). In pre-ovulatory follicles after
induced luteolysis, IGF-I concentrations increase with
oestrogen activity, while intrafollicular amounts of
IGFBPs 2, 4 and 5 are reduced or undetectable
(Echternkamp et al. 1994; Funston et al. 1996). Increa-
ses in IGFBP2 and 5 were seen in pre-ovulatory
follicles following the gonadotrophin surge just before
ovulation, when intrafollicular progesterone rises and
both oestradiol and androgens decline (Funston et al.
1996).
194
The role of FSH during follicle wave growth
The FSH dependency of the follicle wave –
cohort growth and subordinate follicle atresia
Following the early demonstration of a peri-ovulatory
FSH rise in cattle (Dobson 1978; Roche and Ireland
1981), associated with emergence of the first follicle
wave of the cycle, it has since become evident that each
emergence of a cohort is causatively linked to the
transient FSH rise (Turzillo and Fortune 1990; Adams
et al. 1993) and that sequential FSH rises associated
with new follicle waves occur during the oestrous cycle
(Adams et al. 1992a; Sunderland et al. 1994), in the
postpartum period (Crowe et al. 1998; Stagg et al. 1998),
and before puberty in cattle (Evans et al. 1994).
Suppression of the periovulatory FSH rise using bovine
follicular fluid blocks emergence of the first follicle wave
(Turzillo and Fortune 1990) yet concurrent administra-
tion of FSH results in wave emergence indicating that
exogenous FSH may be able to override any suppression
of 3–5 mm follicles exerted by other follicles (Bergfelt
et al. 1994a). Administration of exogenous steroids to
cause a more abrupt decline in FSH following its peri-
ovulatory rise will not only delay ultrasound-detectable
emergence of the first follicle wave but also affect the
composition of the wave in relation to intrafollicular
oestradiol, higher MW inhibins and IGF binding
proteins (Austin et al., unpublished data) and lead to a
smaller first-wave DF which shows earlier regression
(Bo et al. 1995). Similarly, delaying the second transient
FSH rise during the cycle using exogenous oestradiol
benzoate will also delay emergence of the second follicle
wave (Bo et al. 1995; O’Rourke et al. 1998). Inhibitory
effects on follicle wave growth following exogenous
oestradiol treatment, however, are difficult to interpret,
as its FSH-suppressive action is only transient and FSH
rises are seen within 2 days of oestradiol treatment
(O’Rourke et al. 2000). New follicle growth may be
severely inhibited when systemic oestradiol concentra-
tions are maintained at 2–3 times follicular phase
concentrations despite rising FSH (Cooke et al.
1997b). It is unknown, whether this is due to the
presence of earlier wave follicles undergoing atresia or a
change in FSH isoforms induced by very high oestradiol
concentrations (Cooke et al. 1997a).
Immunization of heifers against GnRH, which in the
long-term suppresses recurrent FSH rises and abolishes
LH pulses allows antral follicle development to 4 or even
5 mm; however, development from 4 mm requires a rise
in FSH (Prendiville et al. 1995, 1996; Gong et al. 1996;
Crowe et al. 2001). When physiological amounts of
recombinant FSH were administered to GnRH-immun-
ized heifers to induce growth of a follicle wave, multiple
follicles responded but with very low steroidogenic
ability, and DF selection did not occur (Crowe et al.
2001). Thus, ovarian or systemic factors (LH?) other
than FSH may be involved in DF selection and
differentiation.
Subordinate follicle atresia with its concomitant
changes such as reduced oestrogen-activity, reduced
levels of higher MW inhibins and increased amounts of
lower MW IGF binding proteins occurs during the FSH
decline. Prevention of this decline by administration of
M Mihm, MA Crowe, PG Knight and EJ Austin
physiological amounts of FSH delays selection of a DF
in cattle by preventing subordinate follicle atresia and
associated changes in intrafollicular oestradiol, inhibins
and IGF binding proteins (Adams et al. 1993; Mihm
et al. 1997). Thus, less successful cohort follicles are
dependent on elevated FSH concentrations for their
continued growth and oestradiol synthesizing ability;
when FSH is withdrawn more and more follicles initiate
apoptotic changes as FSH drops further below their
requirement threshold. Clearly, the DF is the one follicle
that has become relatively FSH independent and at the
last stage of DF selection it prevents its closest compet-
itor from continued growth by a final reduction in FSH
(Ginther et al. 1999, 2000a,b) (Fig. 1).
FSH and dominant follicles
The FSH decline appears absolutely crucial to DF
selection. When FSH concentrations are maintained
high, morphological DF selection is prevented. Despite
preventing their atresia, the FSH-maintained cohort
follicles show reduced oestrogen-activity and subtle
changes in intrafollicular growth factors compared with
the normally selected single DF; moreover, systemic
oestradiol is not increased despite multiple growing
large follicles (Mihm et al. 1997). Effects of FSH on
in vitro granulosa cell growth factor and steroid synthe-
sis have been shown to differ depending on exposure
levels (Glister et al. 2001). Thus, it is hypothesized that
high FSH may have inhibitory effects on intrafollicular
functions such as oestradiol synthesis preventing full
differentiation of an advanced follicle essential to DF
selection, despite promoting growth and survival of
cohort follicles. In accordance with this hypothesis,
increased levels of FSH receptor and side-chain cleavage
enzyme mRNA were seen in medium follicles belonging
to the first wave when the FSH decline was prevented,
yet large FSH-maintained follicles showed reduced
expression of thecal LH receptor, 17a hydroxylase and
steroidogenic acute regulatory protein mRNA com-
pared with the normally selected single DF (Mihm et al.
2000b). Although the DF has acquired a relatively FSH
independent state, basal FSH concentrations are still
essential to continued survival of the first DF of the
cycle and their withdrawal may predispose the DF to
atresia (Turzillo and Fortune 1993; Bergfelt et al. 2000;
Ginther et al. 2000a).
The role of LH during follicle wave growth
LH and cohort growth
Follicle wave growth and selection of a DF occur in
different LH environments such as during the luteal
phase (1 LH pulse every 3–4 h) or very early postpartum
(1 LH pulse every 6–8h), or even at the onset of the
follicular phase (1 LH pulse every hour) (Rahe et al.
1980, Stagg et al. 1998). Thus it was concluded that
FSH-dependent cohort growth before DF selection is
unaffected by changes in the LH pulse pattern. Inter-
estingly, however, LH shows a transient rise just at the
time when the new DF differentiates itself from its
closest competitor, the largest subordinate follicle
(Kulick et al. 1999). Treatment with progesterone alone
Follicle Wave Growth in Cattle
or in combination with oestradiol during the growth
phase of the first follicle wave of the cycle will reduce or
even abolish LH pulses, yet the timing of selection of the
first DF is similar to control cycles, and the first DF is
selected at a similar size (Adams et al. 1992b; Burke et al.
1994; Ginther et al. 2001). Subsequently, however,
growth of the DF is affected with increased amounts
of IGFBP2 in follicular fluid, reduced maximum size
and possibly earlier loss of dominance and atresia
(Burke et al. 1994; Bo et al. 1995; Ginther et al. 2001).
Subtle changes in the composition of the wave regarding
intrafollicular oestradiol, inhibins, free IGF-I and lower
MW IGF binding proteins occurred following the
cessation of LH pulses as a result of exogenous steroid
treatment; however, these changes may be due to
combined effects of a premature FSH decline and
reduced LH pulsatility (Ginther et al. 2001; Austin
et al. unpublished data). Conversely, when LH pulses
were administered to the emerging first follicle wave, no
differences in DF selection, gonadotrophin receptor and
steroidogenic enzyme gene expression were seen (Crowe
et al. 2000). Interestingly, administration of LH pulses
to follicles induced to grow by recombinant FSH in the
GnRH immunized heifer model markedly increased
follicular oestradiol synthesizing ability (Crowe et al.
2001), and administration of LH is considered essential
to stimulate FSH-induced follicles to grow beyond
9 mm in diameter in the GnRH-agonist treated heifer
model (Gong et al., 1996). In fact, when FSH was
maintained high to prevent DF selection following
emergence of the first follicle wave of the cycle, the loss
in differentiation and thecal functions seen in artifically
maintained cohort follicles was overcome by treatment
with LH pulses which again increased steroidogenic
ability to and beyond levels seen in the normally selected
single DF (Crowe et al. 2000). Thus, it appears that only
the cohort follicle which became the DF attained the
ability to enhance its thecal functions and thus the
production of precursors for oestradiol synthesis during
declining FSH by enhancing its response to the two
gonadotrophins (possibly via inhibins and IGF) inde-
pendent of the LH environment.
LH and the dominant follicle
Subsequent to its selection, however, the fate of the DF,
its oestrogen activity and period of dominance are
ultimately controlled by LH, in particular the LH pulse
pattern. Administration of LH pulses during the luteal
phase will prolong the dominance phase of the first wave
DF (Taft et al. 1996) while treatment with an GnRH
antagonist during growth of the first follicle wave not
only abolishes LH pulses, but also reduces the size and
dominance periods of the first and second DFs (Fike
et al. 1997). Dominant follicles selected during early
postpartum do not usually ovulate, yet can be stimula-
ted to secrete more oestradiol using exogenous LH
pulses, which will cause an oestradiol surge inducing the
gonadotrophin surge and ovulation (Duffy et al. 2000).
Increased LH pulse frequencies seen following prog-
estagen treatments will prolong the period of dominance
of DFs (Savio et al. 1993; Stock and Fortune, 1993;
Mihm et al. 1999), while atresia can be reliably caused in
195
artifically maintained DFs by an acute decrease in LH
pulse frequency using exogenous progesterone (Savio
et al. 1993; Rajamahendran and Manikkam 1994), GnRH
antagonist (Manikkam et al. 1995) or oestrogen (Yelich
et al. 1997). Dominant follicle atresia occurs with an
associated decrease in intrafollicular oestradiol and free
IGF-I, increases in lower molecular weight IGFBPs and
granulosa cell apoptosis (de la Sota et al. 1996; Stewart
et al. 1996; Manikkam and Rajmahendran 1997; Ginther
et al. 2001).
Dependency of pituitary FSH secretion
on the follicle wave
Growth of a follicle wave and the DF causes declining
and nadir FSH
The transient FSH rises occurring at regular 8–10-day
intervals in cattle of differing reproductive states are
essential to follicle wave growth, and this raises two
questions which need to be addressed in order for
hormonal manipulation of follicle wave growth to
become more successful: first, are cohort growth, DF
selection and loss of dominance solely responsible for
rising and declining FSH, and thus DF selection?
Secondly what are the specific components of follicular
secretions that regulate FSH secretion from the pituit-
ary? The first question relates to the relative contribu-
tion of the hypothalamus vs ovarian secretions in the
regulation of FSH secretion from gonadotroph cells
within the pituitary and is so far unresolved. However,
longterm treatment with GnRH agonists or immuniza-
tion against GnRH will abolish transient FSH rises and
thus follicle wave growth (Gong et al. 1996; Prendiville
et al. 1996). In contrast to the immediate effects on LH
pulsatility, the effect on FSH takes approximately
2 months, and may be influenced by changes occurring
in dominant follicles which turn over at minimum
intervals.
There is no doubt that the regular fluctuations in
follicular/ovarian secretions are to a large extent
responsible for the changes seen in FSH baseline. Loss
of dominance of a DF during the luteal phase or an
artificially maintained DF causes an increase in FSH
concentrations and a new follicle wave can be detected
just at the time of the FSH maximum (Sunderland et al.
1994; Manikkam and Rajamahendran 1997). Removal
of the selected DF using ultrasound-guided ablation
causes a rapid increase in FSH concentrations between
4 and 12 h after the ablation followed by emergence of
the next follicle wave within 2 days of ablation (Fig. 4a;
Bergfelt et al. 1994b; Ginther et al. 1999). During the
first half of the FSH decline growth of cohort follicles
occurs beyond 5 mm accompanied by increased intra-
follicular oestradiol and higher MW inhibins in the
largest follicles (Austin et al. 2001). The extent of the
FSH decline is also directly related to the number of
growing cohort follicles, most rapidly occurring when
the complete wave is allowed to progress and select a
DF, while the decline is inhibited by continuous
aspiration of cohort follicles following their emergence
(Gibbons et al. 1999). Subsequent to its selection, the
DF maintains FSH at nadir concentrations (Fig. 4a)
which is below the FSH requirements of smaller follicles
196
Fig. 4. Serum concentrations (mean
SEM) of (a) FSH, (b) oestradiol
and (c) inhibin-A in control cycles (n ¼ 10 for FSH and oestradiol;
n ¼ 6 for inhibin-A; ) and in cycles, in which the dominant follicle
was ablated on day 5 (n ¼ 4–5; ) (D0 ¼ oestrus)
thus preventing emergence of a new follicle wave
(Ginther et al. 2000b).
Follicular secretions
Ablation of the first wave DF causes a rapid reduction in
systemic oestradiol associated with rising FSH, and thus
ovarian oestradiol secretions are at least partly respon-
sible for suppression of FSH (Fig. 4b,c; Ginther et al.
2000b). As mentioned above, however, exogenous
oestradiol only exerts a transitory inhibitory effect on
pituitary FSH secretion (Cooke et al. 1997b; O’Rourke
et al. 2000) and oestradiol alone is unable to suppress
post-ovariectomy elevated FSH to pre-ovariectomy con-
centrations (Findlay and Clarke 1987). During loss of
M Mihm, MA Crowe, PG Knight and EJ Austin
dominance, oestradiol secretion from the first wave DF
can be reduced from day 6 of the cycle, while FSH
concentrations do not rise until days 7–9 (Sunderland
et al. 1994), thus indicating that oestradiol does not
regulate systemic FSH on its own. An injection of bovine
follicular fluid or highly purified bovine inhibin decreased
plasma concentrations of FSH in ovariectomized (Beard
et al. 1990) and cyclic heifers (Quirk and Fortune 1986),
indicating that inhibin and other follicular fluid compo-
nents have the ability to suppress FSH secretion in cows
in vivo. Thus, emergence of the next wave is delayed in
cattle when bovine follicular fluid or purified inhibin are
administered during the peri-ovulatory FSH rise or at
induced luteolysis (Beard et al. 1990; Turzillo and
Fortune 1990; Adams et al. 1992a), and continued growth
of the first wave DF can be affected when treatments are
administered during its dominance period (Adams et al.
1992a; Turzillo and Fortune 1993; Bergfelt et al. 2000;
Ginther et al. 2000a). However, a delay in emergence of
the ovulatory follicle wave following induced luteolysis
was also seen in inhibin-immunized animals treated with
bovine follicular fluid, and thus it is concluded that
follicular fluid contains other FSH suppressing factors
such as follistatin (Wood et al. 1993). As immunoneu-
tralization of endogenous inhibin during the early and
mid-luteal phases of the bovine oestrous cycle results in a
marked and selective increase in plasma concentration of
FSH, it is concluded that follicular inhibin must be an
important factor in the regulation of FSH secretion in
cattle (Kaneko et al. 1993, 1997; Glencross et al. 1994).
Changes in systemic inhibin during follicle wave growth
Only one study has so far investigated the relationship
between systemic inhibin-A, FSH, oestradiol and follicle
growth in cattle (Bleach et al. 2001). Following a rise in
mean inhibin-A during pre-ovulatory follicle develop-
ment, inhibin-A dropped after the gonadotrophin surge
coincident with the peri-ovulatory transient FSH rise.
During the subsequent 3 days when the first follicle wave
emerged and the DF grew, inhibin-A increased coinci-
dent with systemic oestradiol, while FSH concentrations
were reduced by approximately 50%. Thereafter, both
inhibin-A and oestradiol declined despite the fact that
the first DF continued to grow, presumably reflecting
loss of functional dominance, which is associated with a
marked increase in FSH. Growth of the next follicle
wave and DF was again associated with a three-fold rise
in inhibin-A and a five-fold rise in oestradiol. Prelim-
inary analysis of a subsequent study confirmed the
inhibin-A pattern during growth of the first follicle
wave, with maximum concentrations being attained on
day 3.5 of the cycle before DF selection, and a slow
decline reaching nadir concentrations at the time of
maximum FSH preceding emergence of the next follicle
wave (Mihm et al. 2001). This pattern appears to reflect
the acquisition and subsequent maintenance of the
ability to synthesize higher MW inhibins by successful
cohort follicles 33 and 53h after the FSH maximum
(Austin et al. 2001). No further changes in intrafollicular
amounts of the higher MW inhibins were seen in the
selected DF, and it is, therefore, concluded that the
detection of high inhibin-A concentrations in circulation
Follicle Wave Growth in Cattle
reflects the presence of successfully growing follicles but
does not differentiate between multiple cohort or single
dominant follicles. Confirming this hypothesis, a rapid
decline in circulating inhibin-A was detected when either
the first dominant follicle was ablated or cohort follicles
were made atretic using exogenous steroid treatments
(Fig. 4c; Mihm et al. 2001). We, therefore, conclude in
accordance with Ginther et al. (1996) that a reduction in
concentrations in both follicular secretions, oestradiol
and inhibin-A, contributes to the generation of the
next transient FSH rise required to initiate the FSH-
dependent growth of a new follicle wave.
Conclusions
Follicle wave growth and DF selection in cattle are
acutely dependent on transient FSH rises and the
subsequent FSH decline, which causes the differenti-
ation of the cohort into successful (ultimately the DF)
and unsuccessful (subordinate) follicles according to
their individual FSH requirement thresholds. Mainten-
ance of high levels of higher MW inhibins reflected by
high systemic inhibin-A, and low levels of lower MW
IGF binding proteins, as well as enhanced thecal cell
functions appear essential to DF differentiation during
the FSH decline. Recent research has focused on the
importance of free or bioavailable IGF during the
selection process, and in particular changes in thecal
IGFBP4 and its specific protease, a granulosa cell
product, during DF selection may become important
as predictors of dominance. The ability of wave
follicles to grow and differentiate is possibly affected
by the preceding systemic and ovarian environment,
and the role of other (healthy or atretic) follicles
present still needs to be explored. Hormonal manipu-
lations of follicle wave growth have utilized the
dependency of wave follicles on both gonadotrophins
yet still lack consistency and predictability of the
follicular response. Premature suppression of transient
FSH rises will immediately cause intrafollicular chan-
ges in the growing cohort, but may only delay follicle
wave emergence. Dominant follicle atresia can be
reliably induced via reduction of the LH pulse
frequency, however, a delay of several days occurs
until emergence of the next wave. Clearly, further
understanding is required regarding the differential
gonadotrophin response of growing cohort and dom-
inant follicles in order to successfully control follicle
wave growth in cattle of differing reproductive states.
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exogenous oestrogen treatment in beef cattle. J Anim Sci 75,
745–754.
Submitted: 28.03.2002
Authors’ address (for correspondence): M. Mihm, Department of
Veterinary Preclinical Studies, University of Glasgow Veterinary
School, Bearsden Road, Glasgow G61 1QH, UK.
E-mail: m.mihm@vet.gla.ac.uk