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Theriogenology 73 (2010) 488–495

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Ovarian stimulation with follicle-stimulating hormone under

increasing or minimal concentration of progesterone in dairy cows
T.M. EL-Sherry a,b,*, M. Matsui b, K. Kida c, A. Miyamoto d, G.A. Megahed a,
S.H. Shehata a, Y-I. Miyake b
a
Department of Theriogenology, Assiut University, Assiut, Egypt
b
Department of Clinical Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
c
Field Centre of Animal Science and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
d
Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
Received 30 June 2009; received in revised form 10 September 2009; accepted 27 September 2009

Abstract
The objective of this study was to investigate the effect of the presence or absence of Corpus luteum (CL) on the follicular
population during superstimulation in dairy cows (Holstein-Friesian cattle). Animals were divided into two groups as follows: (1)
Growing CL group (G1): Cows (n = 7) received a total dose of 28 Armour units (AU) follicle-stimulating hormone (FSH) through
the first 4 d (twice daily) after spontaneous ovulation (Day 0). (2) CL Absence group (G2): Cows (n = 10) received prostaglandin
F2a (PGF2a) at 9 or 10 d after ovulation. After 36 h, all the follicles (larger than 5 mm) were aspirated (Day 0). The FSH treatment
started 24 h after aspiration and continued for 4 d. The number of small (3 to <5 mm), medium (5 to <8 mm), and large (8 mm)
follicles was examined on Days 1, 3, and 5 in all groups. Blood samples were collected daily for 5 d, and progesterone (P4), estradiol
(E2), insulin-like growth factor-1 (IGF-1), and growth hormone (GH) in plasma were measured by enzyme immunoassays. The
results showed that in G1, the P4 level increased gradually from 0.5 ng/mL at Day 1 to 2 ng/mL at Day 5, whereas in G2, the P4 level
was completely below 0.5 ng/mL. All cows of the G2 group showed an increase of E2 at Day 3 or Day 4 followed by an increase of
IGF-1 within 24 h, while GH increased concomitantly with the E2 increase in 8 of 10 trials. On the other hand, cows of the G1 group
showed neither E2 nor IGF-1 increase. Moreover, at the end of the treatment, the number of follicles in the G2 group was
significantly increased compared with that of the G1 group (22.8  2.0 vs. 11.6  2.0). In conclusion, low P4 level during FSH
treatment enhanced multiple follicular growth and E2 secretion, which was followed by increase of IGF-1 and GH. Therefore, the
absence of the CL may play a critical role in the superovulation response by controlling the number of growing follicles.
# 2010 Elsevier Inc. All rights reserved.

Keywords: Cattle; GH; Follicle; Progesterone; IGF-1; Superovulation

1. Introduction idea supporting this recommendation was the emergence

Traditionally, superovulation has been recommended
to be performed at Day 9 or 10 of the estrous cycle. The
* Corresponding author. Tel.: +2 088 2334699;
fax: +2 088 2 366503.
E-mail address: timorsherry@yahoo.com (T.M. EL-Sherry).
of the second follicular wave [1,2]. At that time, the
presence of a functional corpus luteum was confirmed to
prevent endogenous luteinizing hormone (LH) surge [3].
Many factors have been controlled to improve the
number of growing follicles and consequently increase
the number of collected embryos. The time of follicular
wave emergence [4,5] and the presence of the dominant
follicle [6,7] are two important factors playing notable

0093-691X/$ – see front matter # 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.theriogenology.2009.09.031
 T.M. EL-Sherry et al. / Theriogenology 73 (2010) 488–495
roles in the success of superovulation, and the levels of
progesterone (P4) [8,9], growth hormone (GH) [10], and
insulin-like growth factor-1 (IGF-1) [11] are other factors
controlling follicular growth. The ablation of the
dominant follicle mechanically [12–15] or physiologi-
cally [16] was one solution to control the variable
response to follicle-stimulating hormone (FSH) treat-
ment and to remove the negative effect of the dominant
follicle on the new follicular wave emergence. Another
way for avoiding the effect of the dominant follicle was to
induce superovulation in the early stage of the first
follicular wave [17,18], which apparently has a different
endocrinologic profile represented by low P4 level. The
use of GH to improve superovulation was confirmed [19].
Moreover, it was found that the number of small follicles
was significantly decreased in cattle with GH-receptors
deficiency [20]. On the other hand, it was found that IGF-
1 works in synergy with FSH and LH to regulate the
proliferation and differentiation of granulosa cells [21].
In this research, we tried to explore the interaction
between GH and IGF-1 under increasing or minimal
levels of P4 and how those factors together with FSH
affect follicular development in dairy cows.
2. Materials and methods
This experiment was carried out at the Field Center
of Animal Science and Agriculture, Obihiro University,
Japan. The nonpregnant, nonlactating, healthy Holstein
cows (Holstein-Friesian cattle) were kept under the
Fig. 1. Timetable of the treatment in each group.
489
normal management program and received mainte-
nance rations.
2.1. Experimental design (Fig. 1)
2.1.1. Growing CL group (G1)
Animals (n = 7) achieved natural ovulation (Day
0 = D0) then received a total dose of 28 Armour
units (AU) porcine FSH (ANTRIN R 10; Kawasaki
Pharm. Co., Kawasaki, Japan) beginning on D1 for 4
successive days (twice daily, 12-h interval) according
to the following dosing schedule: 5, 5; 4, 4; 3, 3; and 2, 2
AU.
2.1.2. CL Absence group (G2)
The animals (n = 10) were synchronized using two
administrations of prostaglandin F2a (PGF2a; Estrumate,
5 mL, Sumitomo Pharm. Co., Osaka, Japan) 11 d apart.
The animals received a third dose of PGF2a by Day 9 or
Day 10 of the new cycle after synchronization cycle
started after second injection with 2–3 days. After 36 h,
all follicles (larger than 5 mm) were aspirated (D0). The
FSH treatment started 24 h after aspiration and continued
for 4 d as in the previous protocol. The follicles 5 mm of
each cow of the G2 group were aspirated by transvaginal
ultrasound-guided follicle aspiration. For the ultrasound
guidance of the aspiration needle, an ultrasound scanner
(SSD-5500; Aloka, Tokyo, Japan) was used that was
equipped with a 7.5-MHz transvaginal convex transducer
490 T.M. EL-Sherry et al. / Theriogenology 73 (2010) 488–495

(UST-M15-21079; Aloka) with an attached 18-gauge, points were analyzed by the Student’s t-test using JMP
single-lumen, stainless steel needle guide. statistical software (version 5.1; SAS Institute, Cary,
NC, USA). The different means were significant at P <
2.2. Monitoring of follicular development 0.05 and P < 0.01. The mean values for all individual
criteria for the GH and IGF-1 area under the curve were
Ultrasound scanning was performed by the same compared from D1 to D5 by the Student’s t-test, and the
operator daily until ovulation for G1 and aspiration for different means were significant at P < 0.05.
G2, then every 48 h starting from Day 1 (D1). To
measure follicle diameter, an ultrasound scanner (SSD- 3. Results
5500; Aloka) equipped with a 7.5-MHz convex
transducer (UST-995-7.5; Aloka) was used. The mean 3.1. Ovarian response to FSH treatment under
diameter of all follicles (>3 mm) through each different level of progesterone
examination was recorded. The observed follicles were
classified into small (3 to <5 mm), medium (5 to The total number of growing follicles was not
<8 mm), and large (8 mm). Scan recorded images significantly different between the G1 and G2 groups at
were stored on a Magneto optical (MO) disk driver D1 (10.4  1.3 vs. 12.4  2.6). However, the follicle
(Maxoplix corporation). number was significantly increased in the G2 group
(20.0  2.1 and 22.8  2.5) at D3 and D5, respectively,
2.3. Blood collection and hormonal determination compared with that for the G1 group (11.3  1.7 and
11.6  1.8, respectively).
The blood samples were collected at D1 and at 24-h
intervals by caudal venipuncture using 10-mL hepar- 3.2. Follicular dynamics
inized tubes. The concentration of P4 were determined by
double-antibody enzyme immunoassays (EIAs) [22]. The number of different-size follicles (mean
The recovery rate was 87%. The standard curve ranged  SEM) at Days 1, 3, and 5 is shown in Fig. 2 within
from 0.05 to 50 ng/mL, and the ED50 (effective dose 50) the same groups. The number of small follicles of the
of the assay was 7.3 ng/mL. Intra-assay and interassay
coefficients of variation (CVs) were 2.9% and 9.3%,
respectively. Enzyme immunoassay for E2 was con-
ducted as described previously [23]. The recovery rate
was 85%. The standard curve ranged from 2 to 2000 pg/
mL, and ED50 of the assay was 126.2 pg/mL. Intra-assay
and interassay CVs were 10.4% and 15.5%, respectively.
The determination of plasma IGF-1 was performed by
EIA as described previously [24]. The standard curve
ranged from 0.39 to 50 ng/mL, and ED50 of the assay was
4.0 ng/mL. Intra-assay and interassay CVs were 3.1%
and 5.6%, respectively. The determination of GH in
plasma was performed by EIA as described previously
[25]. The standard curve ranged from 0.78 to 100 ng/mL,
and ED50 of the assay was 6.2 ng/mL. Intra-assay and
interassay CVs were 5.1% and 11.4%, respectively.

2.4. Statistical analysis

The day of natural ovulation in the G1 group and day

of follicular aspiration in the G2 group was considered
as D0. The plasma concentrations of P4, E2, GH, and
IGF-1 were analyzed by repeated-measures ANOVA to
determine main effects of group, day, and group by day.
When main effect of group or group by day was
observed, the difference of group means at specific time
Fig. 2. Changes in the number of small (3 to <5 mm), medium (5 to
<8 mm), and large (8 mm) follicles at D1, D3, and D5 between the
two groups. Values are mean  SEM of each time period. a,bSigni-
ficant at P < 0.05 between groups. x,ySignificant at P < 0.05 between
the same category of follicles within the same group.
 T.M. EL-Sherry et al. / Theriogenology 73 (2010) 488–495 491

Fig. 3. Comparative changes in the plasma concentration of (A) P4, (B) E2, (C) GH, and (D) IGF-1 in the two groups. Blood samples were collected
daily from D1 to D5. Values are mean  SEM of each time period. a,bSignificant difference at P < 0.05 between groups.

G1 group at D1 was significantly higher than the
number of small follicles on D3 and D5. On the other
hand, the number of large-size follicles at D5 was
significantly than the number of large follicles at D1 and
D3. In the G2 group, the number of small follicles was
significantly higher than those of D3 and D5, whereas
the number of middle-size follicles showed no
significant difference between the days of treatment.
The number of large-size follicles was significantly
increased at D5 in comparison with that of D1 and D3.
Between the groups, it was found that the number of
middle-size follicles at D3 in the G2 group (10.4  1.4)
was greater than that in the G1 group (3.7  0.9;
P < 0.05). Furthermore, at D5, the number of large-size
follicles in the G2 group (19.4  2.0) was also greater
than that in the G1 group (10.0  1.9; P < 0.05)
(Fig. 2).
3.3. Comparison of the hormonal profile between
both groups
D4 to D5 with a mean concentration of 0.29  0.02 ng/
mL.
3.3.2. Estradiol
The analysis of E2 from D1 to D5 revealed an effect
of group by day (P < 0.01; Fig. 3B). In the G1 group,
the E2 increased above 2 pg/mL at D2 to D4 and then
decreased gradually. In contrast, in the G2 group, the
animals showed three patterns of E2: some animals
showed a peak at D3 (n = 4; two of them showed signs
of heat) or D4 (n = 4; one of them showed signs of heat),
and some animals showed no peak at all (n = 2) (Fig. 4).
3.3.3. Growth hormone
Although the GH profile from D1 to D5 showed no
effect of group or group by day (Fig. 3C), the GH of the
G2 group was significantly increased at D4. Moreover,
the area under the curve from D1 to D5 was significantly
increased in the G2 group in comparison with that in the
G1 group.

3.3.1. Progesterone 3.3.4. Insulin-like growth factor-1

The analysis of P4 from D1 to D5 revealed an effect
of group (P < 0.01) and an effect of group by day
(P < 0.01; Fig. 3A). In the G1 group, the P4 gradually
increased at D3. On the other hand, P4 in the G2 group
was significantly lower than that in the G1 group from
There was a significant effect of group by day for
IGF-1 (Fig. 3). In the G1 group, IGF-1 had no change
through days of treatment. In the G2 group, the
peripheral IGF-1 showed a significant increase starting
from Day 3 to Day 5.
492 T.M. EL-Sherry et al. / Theriogenology 73 (2010) 488–495
Fig. 4. Hormonal profiles of P4, E2, GH, and IGF-1 in the G2
subgroups: D3 Peak (n = 4), D4 Peak (n = 4), and No Peak (n = 2).
3.3.5. G2 subgroups
According to the E2 peak, G2 was classified into
three subgroups: D3 Peak, D4 Peak, and No Peak.
The follicular dynamics of the G2 subgroups is
demonstrated in Fig. 5. It was found that the D3 Peak
subgroup had a higher number of the medium and
large follicles at D3 and D5, respectively, followed by
the D4 Peak subgroup. In contrast, the No Peak
subgroup had the lowest number of medium and large
follicles at D3 and D5, respectively. The animals
belonging to the G2 group showed three different
patterns of GH concentration: a peak of GH at D3, at
D4, or no peak. These patterns almost followed those
of E2 (Fig. 4).
Fig. 5. Comparative changes in the number of small (3 to <5 mm),
medium (5 to <8 mm), and large (8 mm) follicles in D1, D3, and D5
between the G2 subgroups. Values are mean  SEM of each time
period. a,bSignificant at P < 0.05 between groups.
4. Discussion
In previous reports, multiple follicular growth was
obtained by FSH treatment in the first follicular wave
[4,17,18]. The current study clearly showed that
follicular recruitment occurred after follicle aspiration
in the G2 group, similar to the follicular recruitment
after spontaneous ovulation in the G1 group. However,
the total number of growing follicles at D3 and D5 was
significantly higher in the G2 group than in the G1
group. The number of small follicles decreased in both
G1 and G2 groups from D1 to D3. The number of large
follicles increased at D3 in the G2 group, but it did not
change in the G1 group. These results indicated that the
follicular growth from small to middle and from middle
to large in the G2 group was greater than that in the G1
group at an early period of the follicular wave.
Improved follicular growth in the G2 group may be
caused by stimulation of follicular growth under a low
level of P4. Follicle aspiration enhances endogenous
 T.M. EL-Sherry et al. / Theriogenology 73 (2010) 488–495
increase of FSH, which was associated with the follicle
emergence [26,27]. This endogenous FSH increase may
be overlapped with the external FSH treatment and
together make the concentration of the plasma FSH in
the G2 group higher than that of the G1 group.
The P4 level showed two different patterns. In the G1
group, the plasma P4 level increased gradually and
concomitantly with growth of the cyclic CL. This P4
pattern represents the normal P4 level in the early stage
of the estrous cycle [28]. In the G2 group, on the other
hand, the follicular aspiration before the LH surge
suppresses CL formation and maintains nadir P4
concentration during the follicular wave [29].
The results demonstrated that concentrations of E2,
GH, and IGF-1 were modulated by the different P4
patterns. In the G1 group, the E2 concentration was
lower than that in the G2 group. This may be related to
the ascending pattern of P4 in the G1 group, which may
suppress the LH secretion [30], which in turn reduced
the size of the large follicles [31,32] and or reduced the
aromatase activity of the granulosa cells [33].
In the G2 group, and because of the absence of P4,
the animals showed an elevation of E2, and even some
animals showed signs of heat. The reasons for the high
E2 level may be related to the increase in number of
growing follicles and/or the increase of the level of E2
production. The low P4 treatment caused an increase in
the aromatase activity of granulosa cells in cows, which
consequently increased the E2 in the follicular fluid
[33]. Previous studies demonstrated that P4 modulated
the LH secretion, which in turn had an influence on the
follicular dynamics and steroidogenesis [34–36].
Although the patterns of LH secretion in both groups
were not determined in the current study, the relation
between low P4 concentration and the increase in the
LH pulse frequency was confirmed previously [9,30]. It
is possible that modified secretion of LH under low P4
may have enhanced the growth and steroidogenesis of
the follicles in the G2 group.
The peripheral GH concentration was significantly
higher in the G2 group than that in the G1 group. This
increase may be influenced by low P4 and/or high E2
levels. In goat, P4 suppressed the GH pulse amplitude,
frequency, and area under the curve, whereas admin-
istration of E2 increased the GH frequency, amplitude,
and area under the curve [37]. In cattle, it seems that E2
had no direct action on the anterior pituitary to release
GH, but it stimulated the hypothalamus to release
Growth hormone releasing hormone (GHRH) [38].
The results revealed that IGF-1 started to increase
from D3 to D5 in the G2 group, which seemed to be
associated with the increase of E2 and/or GH. It was
493
reported that IGF-1 has been influenced by GH in cattle
[39,40]. Indeed, GH can stimulate the secretion of
hepatic IGF-1, which stimulates follicular growth [20].
Moreover, the addition of GH to bovine granulosa
cultured cells strongly stimulated IGF-1 production
[41]. Insulin-like growth factor-1 is a potent mitogen
that stimulates granulosa cell growth in cow [42] and
increases the sensitivity of follicular cells to LH and
FSH [43] by increasing the FSH receptors expression
[44]. In brief, the exposure of the growing follicles to
systemic and/or local secretion of IGF-1 in the G2 group
would argue that IGF-1 may be involved in the
mechanisms that increase follicular response.
In the G2 subgroups, the interaction of E2 and GH
increased the number of follicles in the D3 Peak and D4
Peak subgroups. It seems that GH plays a role in
enhancement of the follicular number and development.
It was reported that administration of somatotropin
increased the number of small follicles in heifers
[10,19] and increased the response to superovulation in
cow and buffalo [45,46]. Moreover, GH decreased
significantly the incidence of apoptosis in bovine
granulosa cells [41]. Recently, new evidence supports
that GH is involved in the growth of the active dominant
follicle [47]. Growth hormone increased the activity of
steroidogenic enzymes and estradiol secretion during
the follicular phase [48]. These data suggested that the
increase in the expression of Growth hormone receptors
(GHR) may be a turning point for follicles to enter the
ovulatory phase. The same study found that FSH
stimulated the expression of GHR genes in cultured
granulosa cells [47]. From the previous, we propose that
the increase in the number of follicles in the G2 group
was related to the interaction of FSH, E2, and GH,
which together increased the follicular growth and
activity.
According to our data, we hypothesized the
following mechanism (Fig. 6) by which the number
of follicles may get increased in G2: The number of
recruited follicles increased as a result of endogenous
increase of FSH after follicle aspiration, which acted
concomitantly with the external FSH to produce such an
effect. Under the low P4 level, E2 increased as a result of
a high number of growing follicles. This E2 stimulated
GH secretion from the anterior pituitary, which is
released in response to hypothalamic GHRH. Growth
hormone increased the number of growing follicles and
suppressed follicular atresia. Growth hormone and/or
E2 may stimulate the liver to secrete IGF-1. Growth
hormone also stimulated IGF-1 secretion from granu-
losa cells. The interaction of FSH, E2, GH, and IGF-1
may provide a high number of follicles.
494 T.M. EL-Sherry et al. / Theriogenology 73 (2010) 488–495

Fig. 6. Schematic diagram to explain the mechanism by which the number of multiple follicles increased under FSH treatment in low P4 level group.
In the CL Absence group (G2 group), follicular aspiration before LH surge suppressed CL formation and maintained nadir P4 concentration during
the follicular wave. The growing follicles secreted a large amount of E2, which enhanced the GH pulse, which in turn stimulated liver IGF-1
secretion. Follicle-stimulating hormone has a very important role to increase the receptors of FSH and GH. At the same time, GH has an important
role to stimulate more follicles for growth. Furthermore, it decreases the number of atretic follicles. Similarly, IGF-1 has a critical role in the
development of the antral follicle and together with GH may have a role to increase the number of multiple follicles.

In conclusion, in the absence of P4, E2 is considered
as the main key to increase the follicular population by
controlling both GH and IGF-1.
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