Animal Reproduction Science xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Animal Reproduction Science

journal homepage: www.elsevier.com/locate/anireprosci

Review article

Effects of altrenogest on reproductive performance of gilts and

sows: A meta-analysis
⁎
Zhong Wang, Bao Sheng Liu, Xiao Ying Wang, Qing Hui Wei, Huan Tian, Li Qi Wang
College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, 330045, China

A R T IC LE I N F O ABS TRA CT

Keywords: Altrenogest is a synthetic progestogen that allows for synchronization of the time of estrus in
Altrenogest swine. Its effect on reproductive performance, however, is inconsistent due to conflicting data in
Reproductive performance the scientific literature. A meta-analysis of published data, therefore, was performed to determine
Gilts whether altrenogest affects gilt and sow reproductive performance. Altrenogest administration to
Sows
pigs enhanced the number of piglets born alive per litter (NBA), total number born per litter
Meta-analysis
(TNB), estrous rate within 10 days after treatment (ER10) and pregnancy rate (PR) as well as the
farrowing rate (FR) of gilts. The NBA and TNB of primiparous sows fed altrenogest were im-
proved although FR was less. In multiparous sows, altrenogest treatment did not result in any
improvement for any of the five analyzed variables. Additionally, 14-day treatment regimens for
gilts and > 8-days for primiparous sows improved reproductive performance and extent of es-
trous synchrony. The effects of altrenogest on reproductive performance of swine were parity and
treatment duration dependent.

1. Introduction

Altrenogest (allyltrenbolone, 17a-allyl-17b-hydroxy-estra-4,9,11-trien-3-one) is a synthetic progestogen that suppresses ovarian

follicular development. Its primary use is for estrous synchronization in gilts and primiparous sows (Kraeling and Webel, 2015; Lopes
et al., 2017). Altrenogest is used for the precise synchronization of time of estrus at rates up to 93% during 4 to 7 days post
administration (Martinat-Botté et al., 1995; Fernandez et al., 2005). Although in numerous studies there have been attempts to use
altrenogest to improve subsequent reproduction of gilts and sows, there is no clear consensus on the benefits of such treatments. For
example, Martinat-Botté et al. (1990; 1995; 2010) reported that gilts or sows treated with altrenogest had greater farrowing
(88.4% > 80.8%, P < 0.05), estrous (83.4% > 79.6%, P < 0.05) and pregnancy rates (89.3% > 77.4%, P < 0.05) as well as a
larger litter size (9.6 > 9.1, P < 0.05). Nevertheless, in other studies (e.g., Fernandez et al., 2005; van Leeuwen et al., 2011a)
altrenogest treatment had no positive effect and even a negative effect on these reproductive variables. The inconsistency in these
findings might have resulted from small sample sizes or the experimental conditions. Hence, it is necessary to make a systematic and
quantitative assessment of published studies for a comprehensive conclusion.
Over the past few years, meta-analysis, an important method for synthesis of data from previously conducted research, has
become increasingly popular in fields as diverse as medicine, pharmacy, psychology and the social sciences (Böhning et al., 2003; Bax
et al., 2006). This type of analysis has also been used for evaluation of treatment effects in animal science and veterinary medicine.
For example, Chen et al. (2011) investigated the effects of biotin on milk performance of dairy cattle using a meta-analysis. Duffield

⁎
Corresponding author.
E-mail address: wangliqi86@126.com (L.Q. Wang).

https://doi.org/10.1016/j.anireprosci.2018.08.035
Received 20 June 2018; Received in revised form 19 August 2018; Accepted 28 August 2018
0378-4320/ © 2018 Elsevier B.V. All rights reserved.

Please cite this article as: Wang, Z., Animal Reproduction Science, https://doi.org/10.1016/j.anireprosci.2018.08.035
Z. Wang et al. Animal Reproduction Science xxx (xxxx) xxx–xxx

et al. (2008) performed a meta-analysis to ascertain the effect of monensin on metabolism of dairy cattle; and Yan et al. (2016)
assessed efficacy of progesterone supplementation during early pregnancy in cows by a meta-analysis. A well-conducted meta-
analysis provides an unbiased overview of available studies.
Considering the widespread use of altrenogest in pigs and inconsistency of results among studies, a meta-analysis might be helpful
in elucidating effects of altrenogest on subsequent reproduction of pigs after there has been altrenogest treatments and provide
insights as to why there have been inconsistent results among previous studies. In this manuscript, the aim was to evaluate the
efficacy of altrenogest for improving estrous rate within 10 days after treatment (ER10), pregnancy rate (PR), farrowing rate (FR),
number of pigs born alive per litter (NBA) and total number of pigs born per litter (TNB) of gilts and sows, by performing a meta-
analysis of data from all available studies where there was altrenogest administered.

2. Materials and methods

2.1. Search strategy and selection criteria

A comprehensive and systematic search of English literature in Science Direct, Web of Science, PubMed, Ovid, EMA website and
Google Scholar was performed. The keywords used for searching were as follows: “altrenogest and swine”, “altrenogest and pig”,
“altrenogest and gilt”, “altrenogest and sow”, “allyltrenbolone and swine”, “allyltrenbolone and pig”, “allyltrenbolone and gilt”, and
“allyltrenbolone and sow”. Furthermore, citations in the retrieved articles were reviewed to search for additional relevant studies.
Studies were included if (1) these were designed as a randomized controlled trial (RCT) or a clinically controlled trial (CCT); (2)
the population studied was gilts or sows; (3) the dosage of altrenogest was 15–30 mg/d; and (4) all data except for NBA and TBA data
were expressed as either Mean ± SD (standard deviation) or Mean ± SE (standard error). Studies that were not published as full
reports were excluded and conference papers were crosschecked with journal papers to avoid repetition of data.

2.2. Data extraction

Data were extracted independently by two investigators (Z. Wang and L.Q. Wang) and assessed by the other authors.
Discrepancies were resolved by consensus. A template for data extraction including mean, standard deviation, and number of pigs in
each group was drafted. The following data were abstracted from included studies: year, country, number of trails, type of swine,
dose of altrenogest, duration of treatment, number of trial sites, number of animals, breed and reproductive variables including ER10,
PR, FR, NBA, and TNB (Table 1). Weaning-to-estrous interval (WEI) and birth weight (BW) were not analyzed for WEI was calculated
by different intervals in different studies and relevant data for BW were insufficient for meta-analysis. Precision of estimate was based
on the SD values of treated and control groups reported in the publications. If only a SE was provided, SD was calculated by
multiplying the SE of means by the square root of the number of pigs.

2.3. Statistical analysis

A meta-analysis was performed on the extracted data using Stata software (Intercooled Stata V. 12.0; Stata Corp, College Station,
TX, USA). For continuous outcomes, a weighted mean difference (WMD) with 95% confidence interval (95% CI) was calculated. For
dichotomous outcomes, an odds ratio (OR) with 95% confidence interval was calculated. Each study was weighted on the basis of the
inverse of the variance. Statistical significance was considered at P < 0.05. A priori subgroup analyses were conducted based on
parity and treatment duration.
Heterogeneity among studies was assessed using I2-statistic and a guide for interpretation of I² was as follows: 0%–25%, no
heterogeneity; 25%–50%, low heterogeneity; 50%–75%, moderate heterogeneity; 75%–100%, high heterogeneity (Higgins et al.,
2003). A fixed effects model was used if studies were homogeneous and a random effect model was utilized if studies were het-
erogeneous. Forest plots were created to depict means and the confidence intervals in a graphic manner. The WMD in NBA and TNB;
and OR in ER10, PR and FR between altrenogest-treated and control group was the outcome of interest listed in the forest plots. Begg’s
test and funnel plots were used to investigate the publication bias (Begg and Mazumdar, 1994; Sterne and Egger, 2001). The P-
values < 0.05 were considered statistically significant for publication bias.

3. Results

3.1. Identification of studies

There were 358 articles identified from the search of published literature. Only 26 studies met inclusion criteria and this set was
used for meta-analysis. These included studies were from the United States, France, Argentina, Australia, Brazil, New Zealand, Japan,
Canada, Thailand, Ireland, Belgium and Spain (Table 1). Because one study (FDA, 2003) was conducted in the United States and
Canada, 27 locations were included.

3.2. Meta-analysis

Pooled estimations were used to identify effects of altrenogest on gilt and sow reproductive performance. The NBA (WMD = 0.55,

2
 Table 1
Z. Wang et al.

Characteristics of studies used for meta-analysisa.

Study Location Trials, n Type of swine Dose of Duration of Trial Involved Breed Reproductive variables
altrenogest (mg/ treatment (d) sites, n animals, n
d) NBA TNB ER10 PR FR OVR

Pursel et al., 1981 USA 1 Gilts 15 18 1 128 Duroc, hampshire, yorkshire and crossbred ＋ － － － ＋ －
Redmer and Day, 1981 USA 2 Gilts 15 18 1 22 Duroc, hampshire, yorkshire and crossbred － － － － － ＋
Varley, 1983 USA 2 Gilts 16 18 1 60 Landrace × Yorkshire ＋ ＋ － － ＋ －
Davis et al., 1987 USA 2 Gilts 15 14 2 181 Yorkshire, Duroc and crossbred ＋ ＋ ＋ － ＋ －
Martinat-Botté et al., France 1 Gilts 20 18 1 525 — ＋ ＋ － － ＋ －
1990
Rhodes et al., 1991 USA 1 Glits 15 14 1 267 Yorkshire × Duroc, Chester ＋ ＋ － － ＋ ＋
White × Yorkshire × Duroc
Wood et al., 1992 USA 1 gilts and sows 15 14 2 677 Yorkshire, Landrace, and Chester White ＋ － － － － －
Martinat-Botté et al., France 1 Gilts 20 18 1 227 Crossbred ＋ ＋ ＋ ＋ － ＋
1995
Estienne et al., 2001 USA 2 Gilts 15 18 2 181 Landrace × Yorkshire, － － ＋ － ＋ ＋
Hampshire × Landrace × Yorkshire
FDA, 2003 Canada, USA 4 Gilts 15 14 4 320 Crossbred － － ＋ ＋ ＋ －
Shimatsu et al., 2004 Japan 1 Gilts 15 18 1 20 Miniature pigs ＋ － － － － ＋
Kaeoket, 2008 Thailand 1 Gilts 20 18 1 30 Landrace × Yorkshire ＋ ＋ － － － －
Boland, 1983 Ireland 1 primiparous sows 20 7 1 69 Yorkshire, Yorkshire × Landrace ＋ － ＋ ＋ － －

3
Stevenson et al., 1985 USA 1 primiparous sows 20 7 1 232 Crossbred ＋ ＋ － ＋ － －
Kirkwood et al., 1986 New Zealand 2 primiparous sows 30 7 and 10 1 68 Yorkshire, Landrace and ＋ ＋ ＋ － － －
Yorkshire × Landrace
Koutsotheodoros et al., Australia 1 primiparous sows 20 12 1 90 Yorkshire × Landrace － － － － － ＋
1998
Everaert et al., 2007 Belgium 1 primiparous sows 20 5 3 1580 — ＋ ＋ － ＋ － －
van Leeuwen et al., Argentina 1 primiparous sows 20 4 1 259 — ＋ ＋ ＋ ＋ ＋ －
2011b
Werlang et al., 2011 Brazil 1 primiparous sows 20 5 1 663 Yorkshire × Landrace, Landrace × Duroc ＋ ＋ ＋ － ＋ －
Chen et al., 2013 Australia 1 primiparous sows 20 7 1 92 Yorkshire, Landrace and Crossbred ＋ ＋ － ＋ ＋ －
Bover and Almond, USA 1 primiparous sows 15 7 1 3063 Landrace × Yorkshire ＋ － － － ＋ －
2014
Kirkwood et al., 1985 New Zealand 1 multiparous sows 20 6 1 21 Landrace × Yorkshire － ＋ － － － －
Dos et al., 2004 Brazil 1 primiparous and 20 4 1 102 Yorkshire ＋ ＋ － ＋ － －
multiparous sows
Patterson et al., 2008 USA 1 multiparous sows 15 7 and 14 1 749 Crossbred － － － － － ＋
van Leeuwen et al., Argentina 1 primiparous and 20 7 1 217 — ＋ ＋ ＋ － ＋ －
2011a multiparous sows
Lopes et al., 2017 Spain 1 primiparous and 20 6 1 71 Landrace × Yorkshire － ＋ － － ＋ －
multiparous sows

a
NBA = number of pigs born alive per litter; TNB = total number of pigs born per litter; ER10 = estrous rate within 10 days after treatment; PR = pregnancy rate; FR = farrowing rate;
OVR = ovulation rate; – =data not available; + =matched.
Animal Reproduction Science xxx (xxxx) xxx–xxx
Z. Wang et al. Animal Reproduction Science xxx (xxxx) xxx–xxx

P < 0.001) and TNB (WMD = 0.58, P < 0.001) both increased with only small effects on ER10 (OR = 1.16, P = 0.177), PR (OR =
1.15, P = 0.260) and FR (OR = 1.00, P = 0.983). The I2 statistic indicated that heterogeneity for NBA (I2 = 11.4%, P = 0.293), ER10
(I2 = 23.1%, P = 0.197) and PR (I2 = 39.2%, P = 0.072) were not significant. There was a moderate amount of heterogeneity for
TNB (I2 = 48.1%, P = 0.006) and FR (I2 = 47.1%, P = 0.006). The NBA, ER10 and PR data were then applied to a fixed effect model
and a random effect model for TNB and FR (Fig. 1A–D). A Begg’s test for publication bias indicated the lack of any significant
publication bias for the five reproductive variables that were examined (P > 0.05; Table 2). An example of a funnel plot for the
studies of the altrenogest effect on NBA in gilts and sows (Fig. 2) indicated there was a symmetrical distribution of the studies,
indicating that no publication bias existed among studies.

3.3. Effects of altrenogest on reproductive performance of gilts

Meta-analysis for each reproductive variable in gilts indicated that altrenogest treatment improved performance by increasing
NBA (WMD = 0.48, P < 0.001), TNB (WMD = 0.53, P < 0.001), ER10 (OR = 1.52, P = 0.023), PR (OR = 2.21, P = 0.005) and FR
(OR = 1.56, P = 0.001; Table 3). Gilts were treated with altrenogest for 14 or 18-days so this effect was investigated by analyzing
each separately. Both the 14- and 18-day treatments improved all values for all variables except for PR in the 14-day group and ER10
in the 18-day group. Interestingly, results indicated there was a trend that gilt reproductive performance with 14-day treatment was
greater than that of the 18-day group (Table 4).

3.4. Effects of altrenogest on reproductive performance of primiparous sows

The variations in values for each reproductive variable in primiparous sows indicated that NBA (WMD = 0.67, P < 0.001) and
TNB (WMD = 0.77, P = 0.002) were increased. There, however, was no improvement in ER10 (OR = 1.01, P = 0.506), and a
decrease in FR (OR = 0.79, P = 0.047) and a non-significant decrease in PR (OR = 0.84, P = 0.430) (Table 5). These results
indicated that for primiparous sows, altrenogest had a positive effect on NBA and TNB and no or a negative effect on the values for
other reproductive variables.
There was an assessment of the effect of altrenogest treatment duration on the five reproductive variables in primiparous sows.
The studies could be subdivided into a 3–5 day groups, a 6–8 day groups and a ＞8 day group. With the shortest treatment (3–5 days),
there was no effect for all five reproductive variables. In the 6–8 day group, NBA (WMD = 0.62, P < 0.001) and TNB (WMD = 0.60,
P = 0.032) were greater. The FR (OR = 0.79, P = 0.012), however, was less and ER10 and PR were not different between treated and
non-treated animals. For the ＞8 day group, there was an increase in NBA (WMD = 1.24, P = 0.001) and TNB (WMD = 2.12,
P < 0.001) but no difference in FR, ER10 and PR compared to controls (Table 6). Treatment for 3–5 days, therefore, had no effect,
while treatment for 6–8 days and for more than 8 days both had a positive effect on NBA and TNB. Treatment for 6–8 days, however,
had a negative effect on FR. These results indicated that primiparous sows in the > 8 day treatment group had greater NBA and TNB
scores than those in the 6–8 day group.

3.5. Effects of altrenogest on reproductive performance of multiparous sows

Reports where there was no distinguishing between primiparous and multiparous sows were included for this analysis. As in-
dicated by data included in Table 7, altrenogest treatment of multiparous sows did not result in any improvement in the reproductive
performance.

4. Discussion

The reproductive performance of gilts and sows is a very important factor for the economic well-being of swine husbandry.
Improving reproductive performance, therefore, increases the economic efficiency of pork production. Altrenogest treatment allows
for synchronization of the time of estrus (Martinat-Botté et al., 1990) and also allows sows to recover from the second-litter syn-
drome, which refers to the decrease in the number of piglets in second litter compared to first litter. The analysis in the present study
indicated that altrenogest enhanced productivity of females through increased litter size. There, however, were large differences in
altrenogest effects on sows of different parities and those with different treatment durations and used these data for subgroup
analysis.

4.1. Effects of altrenogest on reproductive performance of gilts

Treatment with altrenogest improved the reproductive performance by enhancing the values for five reproductive variables that
included NBA, TNB, ER10, PR and FR significantly. Compared to controls, the NBA and TNB of altrenogest-treated gilts increased by
0.53 and 0.48, respectively. Litter size (i.e., NBA and TNB) is a composite variable influenced by ovulation rate, embryonic survival
rate and uterine capacity (He et al., 2017). An increase in litter size with altrenogest treatment has been associated with an increased
ovulation rate (Kirkwood et al., 1986; Martinat-Botté et al., 1995; Koutsotheodoros et al., 1998). In the present study, there was also a
meta-analysis performed on ovulation rate. Because ovulation rate at puberty can be estimated by counting the number of corpora
lutea (Blasco et al., 1998), the studies including these data were regarded as ovulation rate. Treatment with altrenogest increased the
ovulation rate by 1.05 in gilts and 0.43 in primiparous sows Fig. 1(F). Increases in ovulation rate are associated with greater

4
Z. Wang et al. Animal Reproduction Science xxx (xxxx) xxx–xxx

Fig. 1. (continued)

5
Z. Wang et al. Animal Reproduction Science xxx (xxxx) xxx–xxx

(caption on next page)

6
Z. Wang et al. Animal Reproduction Science xxx (xxxx) xxx–xxx

Fig. 1. (continued)

7
Z. Wang et al. Animal Reproduction Science xxx (xxxx) xxx–xxx

Fig. 1. Summary weighted mean difference (WMD; for continuous outcomes) or odds ratios (ORs; and dichotomous outcomes) of the effect of
altrenogest on NBA(A), TNB(B), ER10(C), PR(D), FR(E) and OVR (F) in gilts and sows; NBA, TNB, ER10, PR, FR, and OVR represents number of pigs
born alive per litter, total number of pigs born per litter, estrus rate within 10 days after treatment, pregnancy rate, farrowing rate, and ovulation
rates, respectively; Squares represent study－specific estimates (size of the square is proportional to the weight assigned to the study), the horizontal
lines represent 95% confidence intervals (CIs), the dotted vertical line represents the overall effect size estimate, the solid vertical line represents a
mean difference of zero or no effect; diamonds on the right of the solid vertical line represents positive effect.

progesterone concentrations during the luteal phase of the estrous cycle (Kirkwood et al., 1986). Altrenogest administration induces
an increase in circulating progesterone (Stevenson et al., 1985) and progesterone facilitates ovulation at puberty (Docke and Dorner,
1969).
There was an increase in ER10, PR and FR in altrenogest-treated gilts. This indicated that altrenogest can be used to improve
management practices. For example, the periods of estrus of 85% or more of the estrous cycling gilts treated with altrenogest
occurred in a 5-day interval. The majority of the periods of estrus occur in a 2- to 3-day interval while untreated gilts had a much
greater distribution of periods of estrus (Davis, 2008). More predictable time of onset of estrus could result in more strategic timing of
insemination leading to an improvement in PR, FR and litter size for the treated gilts. Similarly, compared to natural estrus, estrous
synchronization allows for a greater predictability of when estrus will occur. This is most likely the reason for the greater ER10
concentrations in treated gilts.
The duration of altrenogest administration of 14 and 18 days was associated with an improvment of values for all the reproductive
variables that were analyzed in the present study. The 14-day treatment resulted in the greatest overall improvement. Furthermore,
although an 18-day treatment with altrenogest resulted in a more precise synchronization of the timing of estrus in gilts than the 14-
day treatment, > 98% of gilts were in estrus within 3–10 days after the 14-day treatment. This indicated that administration of
altrenogest for 14 days was of a long enough period for corpora lutea to regress and for gilts to synchronously express estrus
(Stevenson and Davis, 1982). A treatment regimen that is 4 days shorter results in a reduction in non-productive days and simplifies
breeding herd management. The 14-day treatment time course is sufficient for synchronization of timing and improvement of re-
productive performance.

4.2. Effects of altrenogest on reproductive performance of primiparous sows

In primiparous sows, altrenogest had positive effects on NBA and TNB and no significant effects on ER10 and PR, and a negative
effect on FR. Besides an increased ovulation rate, greater embryonic survival is likely another reason for a larger litter size in
primiparous sows. Altrenogest administration has a negative feedback on gonadotropin-releasing hormone (GnRH) released from the
hypothalamus. This inhibits follicle stimulating hormone (FSH) and luteinizing hormone (LH) release (Dos et al., 2004) and extends
the interval from weaning to estrus (van Leeuwen et al., 2011b). This can provide a longer recovery period for the reproductive tract
and especially for the endometrium (Svajgr et al., 1974). In addition, second parity sows may have suboptimal litter sizes due to
weight loss during the first lactational period (Soede et al., 2013). In general, sows that have poor performance in the second parity
also have lesser performance in later parities and an increased probability of early culling. A longer post-weaning recovery period
resulting from altrenogest treatment, therefore, might allow for a nutritionally-mediated maximization of pre-ovulatory follicle
development. This would allow time for the optimal oocyte maturation (Koutsotheodoros et al., 1998). Compromised ovarian fol-
liclular development results in lesser quality oocytes and an under developed corpora lutea resulting in increased embryonic losses
(Zak et al., 1997) and eventually smaller litter sizes. Thus, improvement of oocyte quality results in greater embryonic survival and a
larger litter size. Although improved oocyte quality might result in a greater FR (Soede et al., 2013), results of the present study
indicate that there is a negative effect on FR in primiparous sows. The reason for this is unclear and needs further study.
The results of subgroup analysis indicated no significant effect of altrenogest on reproductive performance of primiparous sows
when treated for 3–5 days. There, however, was a positive effect on litter size with 6–8 days of altrenogest treatment that was
reversed in the > 8 day group where there was a negative effect on FR. The LH and FSH released during altrenogest treatment
stimulates follicle growth, but the concentrations are not sufficient to sustain follicle development to pre-ovulatory sizes. In turn,
follicles undergo atresia after 5–8 days of treatment. This might be the reason that extended altrenogest treatments (12–15 days)
resulted in improved fertility and short-term treatments (3–5 days) had little effect on fertility and intermediate treatments (5–8 days)
resulted in reduced fertility (van Leeuwen, 2011). In conclusion, treatment with altrenogest in primiparous sows for longer than 8
days is optimal for improving reproductive performance while synchronizing time of estrus. This would ensure that the treatment
period is long enough to avoid follicle and oocyte aging.

4.3. Effects of altrenogest on reproductive performance of multiparous sows

In multiparous sows, altrenogest treatment after weaning resulted in an increased number of fetuses during pregnancy but the
positive effects were limited by uterine capacity (van Leeuwen et al., 2011a). Relatively greaterovulation rates (> 25) in sows with
more parities result in intra-uterine crowding in early gestation and thereby affects fetal development and losses (Foxcroft et al.,
2006). As a result, there was no improvement in the reproductive performance.

8
Z. Wang et al. Animal Reproduction Science xxx (xxxx) xxx–xxx

Table 2
Summary of the publication bias of each reproductive variablea.
Reproductive variables Coefficient Coefficient 95% CI P-value

NBA 0.135 (-0.498,0.768) 0.665

TNB 0.303 (-0.423,1.029) 0.395
ER10 0.632 (-1.123,2.388) 0.450
PR 0.954 (-1.055,2.962) 0.319
FR 0.626 (-0.458,1.710) 0.244

a
NBA = number of pigs born alive per litter; TNB = total number of pigs born per litter; ER10 = estrous rate within 10 days after
treatment; PR = pregnancy rate; FR = farrowing rate; CI = confidence interval; P-value > 0.05 means that there is no publication bias.

Fig. 2. Funnel plot of altrenogest effect on NBA in gilts and sows, WMD represents weighted mean difference, horizontal line represents overall
effect size estimate, dashed line represents 95% confidence intervals; circles represent individual studies and size of circles is proportional to the
weighting of study.

Table 3
Effects of altrenogest on reproductive performance of gilts derived from meta-analysisa.
Reproductive variables Trials, n Gilts, n WMD or OR (95% CI) I2 Effect size, P-value

Treatment Control

NBA 11 698 695 WMD = 0.48 (0.29, 0.66) 5.40 < 0.001
TNB 8 570 561 WMD = 0.53 (0.34, 0.73) 16.6 < 0.001
ER10 5 453 427 OR = 1.52 (1.06,2.19) 15.6 0.023
PR 2 250 235 OR = 2.21(1.26,3.85) 0.00 0.005
FR 10 701 743 OR = 1.56 (1.21, 2.03) 0.00 0.001

a
NBA = number of pigs born alive per litter; TNB = total number of pigs born per litter; ER10 = estrous rate within 10 days after treatment;
PR = pregnancy rate; FR = farrowing rate; WMD = weighted mean difference for continuous outcomes; OR = odds ratio for dichotomous out-
comes; CI = confidence interval.

4.4. Limitations

The present study has several potential limitations. First, the possibility of information and selection biases and unidentified
confounders cannot be completely excluded because most of the included studies were observational. Second, only five variables of
reproductive performance in gilts and sows were included in the present study. Other variables that have been shown to be sig-
nificantly associated with altrenogest treatment, such as weaning to estrus interval and embryonic survival rate, were not included
because limited data were available. Third, the search strategy in the present study was restricted to articles published in English.
Articles with potentially high-quality data that were published in other languages were not included because of anticipated diffi-
culties in obtaining accurate medical translation.

5. Conclusions

Results of the present study demonstrate that altrenogest treatment of gilts improved the reproductive performance by increasing
the NBA, TNB, ER10, PR, and FR. Treatment for 14 days is an acceptable duration considering of effect, cost and convenience. In
primiparous sows, altrenogest enhanced NBA and TNB, and reduced FR. Treatment for more than 8 days is recommended to improve
the reproductive performance when synchronizing time of estrus. Altrenogest treatment, however, was ineffective in improving

9
Z. Wang et al. Animal Reproduction Science xxx (xxxx) xxx–xxx

Table 4
Effects of duration of altrenogest treatment on reproductive performance of gilts derived from meta-analysisa.
Reproductive variables Treatment duration,d Trials, n Gilts, n WMD or OR (95% CI) I2 Effect size,
P-value
Treatment Control

NBA 14 4 216 190 WMD = 0.52 (0.13,0.90) 0.00 0.008

18 7 482 505 WMD = 0.46 (0.24,0.68) 32.4 < 0.001
TNB 14 3 153 130 WMD = 0.62 (-0.02,1.26) 45.2 0.057
18 5 417 431 WMD = 0.50 (0.35,0.66) 7.80 < 0.001
ER10 14 3 299 294 OR = 1.57 (1.06,2.33) 32.8 0.025
18 2 142 133 OR = 1.29 (0.53,3.15) 35.6 0.573
PR 14 1 126 132 OR = 1.92 (0.82,4.49) – 0.131
18 1 124 103 OR = 2.45 (1.17,5.14) – 0.017
FR 14 4 297 296 OR = 1.67 (1.16,2.40) 0.00 0.006
18 6 404 447 OR = 1.47 (1.01,2.12) 0.00 0.042

a
NBA = number of pigs born alive per litter; TNB = total number of pigs born per litter; ER10 = estrous rate within 10 days after treatment;
PR = pregnancy rate; FR = farrowing rate; – = data was not available; WMD = weighted mean difference for continuous outcomes; OR = odds
ratio for dichotomous outcomes; CI = confidence interval.

Table 5
Effects of altrenogest on reproductive performance of primiparous sows derived from meta-analysisa.
Reproductive variables Trials, n Sows, n WMD or OR (95% CI) I2 Effect size, P-value

Treatment Control

NBA 14 2024 2066 WMD = 0.67 (0.48, 0.86) 8.10 < 0.001
TNB 11 464 474 WMD = 0.77 (0.28, 1.27) 56.6 0.002
ER10 9 856 886 OR = 1.01 (0.77,1.32) 24.1 0.506
PR 9 312 372 OR = 0.84 (0.54,1.30) 40.6 0.430
FR 11 2584 2587 OR = 0.79 (0.62,1.00) 37.7 0.047

a
NBA = number of pigs born alive per litter; TNB = total number of pigs born per litter; ER10 = estrous rate within 10 days after treatment;
PR = pregnancy rate; FR = farrowing rate ; WMD = weighted mean difference for continuous outcomes; OR = odds ratio for dichotomous out-
comes; CI = confidence interval.

Table 6
Effects of duration of altrenogest treatment on reproductive performance of primiparous sows derived from meta-analysisa.
Reproductive variables Treatment duration, d Trials, n Sows, n WMD or OR I2 Effect size,
(95% CI) P-value
Treatment Control

NBA 3–5 6 204 236 WMD = 0.36 (-0.20,0.93) 0.00 0.210

6–8 7 1855 1788 WMD = 0.62 (0.41,0.82) 0.00 < 0.001
＞8 4 135 140 WMD = 1.24 (0.50,1.99) 53.6 0.001
TNB 3–5 5 186 211 WMD = 0.15 (0.30,0.60) 3.10 0.526
6–8 7 359 267 WMD = 0.60 (0.05,1.14) 54.8 0.032
＞8 3 95 105 WMD = 2.12 (1.23,3.12) 0.00 < 0.001
ER10 3–5 6 713 719 OR = 0.98 (0.73,1.31) 50.5 0.894
6–8 3 143 167 OR = 1.64 (0.57,2.56) 0.00 0.165
＞8 1 101 29 OR = 0.37 (0.02,7.02) – 0.506
PR 3–5 5 156 197 OR = 0.70 (0.38,1.28) 52.3 0.249
6–8 4 351 362 OR = 0.91 (0.61,0.34) 38.4 0.012
＞8 2 37 48 OR = 1.33 (0.84,2.11) 0.00 0.231
FR 3–5 6 839 846 OR = 0.83 (0.581.20) 51.7 0.325
6–8 7 1856 1782 OR = 0.79 (0.65,0.95) 0.00 0.012
＞8 1 55 63 OR = 2.17 (0.53,8.82) – 0.280

a
NBA = number of pigs born alive per litter; TNB = total number of pigs born per litter; ER10 = estrous rate within 10 days after treatment;
PR = pregnancy rate; FR = farrowing rate; – = data was not available; WMD = weighted mean difference for continuous outcomes; OR = odds
ratio for dichotomous outcomes; CI = confidence interval.

10
Z. Wang et al. Animal Reproduction Science xxx (xxxx) xxx–xxx

Table 7
Effects on reproductive performance of multiparous sows or primiparous＋multiparous sows treated with altrenogesta.
Reproductive variables Trials, n Sows, n WMD or OR (95%CI)I2 I2 Effect size, P-value

Treatment Control

NBA 3 170 98 WMD =−0.18 (−1.02,0.66) 0.00 0.676

TNB 4 176 109 WMD = 0.33 (−0.65, 1.30) 64.9 0.509
ER10 1 101 29 OR = 0.37 (0.02,7.02) – 0.506
PR 2 499 500 OR = 1.07 (0.77,1.50) 0.00 0.678
FR 3 166 104 OR = 0.97 (0.36, 2.60) 0.00 0.952

a
NBA = number of pigs born alive per litter; TNB = total number of pigs born per litter; ER10 = estrous rate within 10 days after treatment;
PR = pregnancy rate; FR = farrowing rate; — = data was not available; WMD = weighted mean difference for continuous outcomes; OR = odds
ratio for dichotomous outcomes; CI = confidence interval.

productive performance of multiparous sows.

Conflict of interest

The authors confirm that they have no conflicts of interest to declare.

Acknowledgements

We acknowledge and appreciate the information that was provided by the referenced authors for this study. This work was
financially supported by Key Research and Development Project of Jiangxi Province (20171BBF60054), and National Natural Science
Foundation of China (31760750).

References

Bax, L., Yu, L.M., Ikeda, N., Tsuruta, H., Moons, K.G., 2006. Development and validation of MIX: comprehensive free software for meta-analysis of causal research data.
BMC Med. Res. Methodol. 6, 50.
Begg, C.B., Mazumdar, M., 1994. Operating characteristics of a rank correlation test for publication bias. Biometrics 50, 1088–1101.
Blasco, A., Sorensen, D., Bidanel, J.P., 1998. Bayesian inference of genetic parameters and selection response for litter size components in pigs. Genetics 149, 301–306.
Böhning, D., Malzahn, U., Schlattmannn, P., Dammann, U., Mehnert, W., Holling, H., Schulze, R., 2003. The application of statistical methods of meta-analysis for
heterogeneity modelling in medicine and pharmacy, psychology, quality control and assurance. In: Jäger, Willi, Krebs, Hans-Joachim (Eds.), Mathematics — Key
Technology for the Future. Springer, Berlin, Heidelberg, pp. 533–553.
Boland, M.P., 1983. Control of oestrus in primiparous sows. Theriogenology 19, 377–384.
Bover, P.E., Almond, G.W., 2014. Use of altrenogest at weaning in primiparous sows. J. Swine Health Prod. 22, 134–137.
Chen, B., Wang, C., Wang, Y.M., Liu, J.X., 2011. Effect of biotin on milk performance of dairy cattle: a meta-analysis. J. Dairy Sci. 94, 3537–3546.
Chen, T.Y., Stott, P., Bouwman, E.G., Langendijk, P., 2013. Effects of pre-weaning energy substitutions on post-weaning follicle development, steroid hormones and
subsequent litter size in primiparous sows. Reprod. Domest. Anim. 48, 512–519.
Davis, D.L., 2008. Using Regumate to Control Estrus in Swine. Swine Day Report of Progress 940. Kansas State University, USA, pp. 11–15.
Davis, D.L., Stevenson, J.S., Pollmann, D.S., Allee, G.L., 1987. Estrous and litter traits in gilts altered by altrenogest, flushing and pubertal status. J. Anim. Sci. 64,
1117–1126.
Docke, F., Dorner, G., 1969. A possible mechanism by which progesterone facilitates ovulation in the rat. Neuroendocrinology 4, 139–149.
Dos, S.J., Wentz, I., Bortolozzo, F.P., Barioni, W.J., 2004. Early-weaned sows: altrenogest therapy, estrus, ovulation, and reproductive performance. Anim. Reprod. Sci.
84, 407–413.
Duffield, T.F., Rabiee, A.R., Lean, I.J., 2008. A meta-analysis of the impact of monensin in lactating dairy cattle. Part 1. Metabolic effects. J. Dairy Sci. 91, 1334–1346.
Estienne, M.J., Harper, A.F., Horsley, B.R., Estienne, C.E., Knight, J.W., 2001. Effects of P.G. 600 on the onset of estrus and ovulation rate in gilts treated with Regu-
mate. J. Anim. Sci. 79, 2757–2761.
Everaert, N., Vanderhaeghe, C., Mateusen, B., Dewulf, J., Van Soom, A., de Kruif, A., Maes, D., 2007. Effects of post-weaning altrenogest treatment in primiparous
sows. Vlaams Diergen. Tijds. 76, 293–299.
FDA, 2003. Freedom of Information Summary. Original New Animal Drug Application NADA 141-222. Altrenogest (MATRIX). (Accessed 17 December 2017). http://
www.docin.com/p-1449914769.html.
Fernandez, L., Diez, C., Ordonez, J.M., Carbajo, M., 2005. Reproductive performance in primiparous sows after postweaning treatment with a progestagen. J. Swine
Health Prod. 13, 28–30.
Foxcroft, G.R., Dixon, W.T., Novak, S., Putman, C.T., Town, S.C., Vinsky, M.D., 2006. The biological basis for prenatal programming of postnatal performance in pigs.
J. Anim. Sci. 84 (Suppl), E105–E112.
He, L.C., Li, P.H., Ma, X., Sui, S.P., Gao, S., Kim, S.W., Gu, Y.Q., Huang, Y., Ding, N.S., Huang, R.H., 2017. Identification of new single nucleotide polymorphisms
affecting total number born and candidate genes related to ovulation rate in Chinese Erhualian pigs. Anim. Genet. 48, 48–54.
Higgins, J.P., Thompson, S.G., Deeks, J.J., Altman, D.G., 2003. Measuring inconsistency in meta-analyses. BMJ 327, 557–560.
Kaeoket, K., 2008. Study on the oestrous synchronization in gilts by using progestin altrenogest and hCG: its effect on the follicular development, ovulation time and
subsequent reproductive performance. Reprod. Domest. Anim. 43, 127–129.
Kirkwood, R.N., Moller, K., Smith, W.C., Lapwood, K.R., Garrick, D.J., 1985. The influence of allyl trenbolone (Regumate) on the timing, duration and endocrinology
of parturition in sows. Anim. Reprod. Sci. 9, 163–171.
Kirkwood, R.N., Smith, W.C., Lapwood, K.R., 1986. Influence of oral administration of allyl trenbolone on subsequent litter size of primiparous sows. New Zealand J.
Exp. Ag. 14, 477–480.
Koutsotheodoros, F., Hughes, P.E., Parr, R.A., Dunshea, F.R., Fry, R.C., Tilton, J.E., 1998. The effects of post-weaning progestagen treatment (Regumate) of early-
weaned primiparous sows on subsequent reproductive performance. Anim. Reprod. Sci. 52, 71–79.
Kraeling, R.R., Webel, S.K., 2015. Current strategies for reproductive management of gilts and sows in North America. J. Anim. Sci. Biotechnol. 6, 3.
Lopes, T., Bolarín, A., Martínez, E., Roca, J., 2017. Altrenogest treatment before weaning improves litter size in sows. Reprod. Domest. Anim. 52, 75–77.

11
Z. Wang et al. Animal Reproduction Science xxx (xxxx) xxx–xxx

Martinat-Botté, F.O., Bariteau, F., Forgerit, Y., Macar, C., Moreau, A., Terqui, M., Signoret, J.P., 1990. Control of oestrus in gilts II. Synchronization of oestrus with a
progestagen, altrenogest (Regumate): effect on fertility and litter size. Anim. Reprod. Sci. 22, 227–233.
Martinat-Botté, F., Bariteau, F., Forgerit, Y., Macar, C., Poirier, P., Terqui, M., 1995. Synchronization of oestrus in gilts with altrenogest: effects on ovulation rate and
foetal survival. Anim. Reprod. Sci. 39, 267–274.
Martinat-Botté, F., Bariteau, F., Forgerit, Y., Macar, C., Poirier, P., Terqui, M., 2010. Control of reproduction with a progestagen—altrenogest (Regumate) in gilts and
at weaning in Primiparous sows: effect on fertility and litter size. Reprod. Domest. Anim. 29, 362–365.
Patterson, J., Wellen, A., Hahn, M., Pasternak, A., Lowe, J., DeHaas, S., Kraus, D., Williams, N., Foxcroft, G., 2008. Responses to delayed estrus after weaning in sows
using oral progestagen treatment. J. Anim. Sci. 86, 1996–2004.
Pursel, V.G., Elliott, D.O., Newman, C.W., Staigmiller, R.B., 1981. Synchronization of estrus in gilts with allyl trenbolone: fecundity after natural service and in-
semination with frozen semen. J. Anim. Sci. 52, 130–133.
Redmer, D.A., Day, B.N., 1981. Ovarian activity and hormonal patterns in gilts fed allyl trenbolone. J. Anim. Sci. 53, 1088–1094.
Rhodes, M.T., Davis, D.L., Stevenson, J.S., 1991. Flushing and altrenogest affect litter traits in gilts. J. Anim. Sci. 69, 34–40.
Shimatsu, Y., Uchida, M., Niki, R., Imai, H., 2004. Effects of a synthetic progestogen, altrenogest, on oestrus synchronisation and fertility in miniature pigs. Vet. Rec.
155, 633–635.
Soede, N., Hoving, L., Leeuwen, J., Kemp, B., 2013. The second litter syndrome in sows; causes, consequences and possibilities of prevention. Acta Bioeth. 16, 155–164.
Sterne, J.A., Egger, M., 2001. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J. Clin. Epidemiol. 54, 1046–1055.
Stevenson, J.S., Davis, D.L., 1982. Estrous synchronization and fertility in gilts after 14- or 18-day feeding of altrenogest beginning at estrus or diestrus. J. Anim. Sci.
55, 119–123.
Stevenson, J.S., Davis, D.L., Pollmann, D.S., 1985. Altrenogest and fat for summer breeding of primiparous sows. J. Anim. Sci. 61, 480–486.
Svajgr, A.J., Hays, V.W., Cromwell, G.L., Dutt, R.H., 1974. Effect of lactation duration on reproductive performance of sows. J. Anim. Sci. 38, 100–105.
van Leeuwen, J., 2011. Post Weaning Altrenogest Use in Sows — Follicle Growth, Endocrine Profiles and Subsequent Fertility. Wageningen University, Netherlands.
van Leeuwen, J.J., Martens, M.R., Jourquin, J., Driancourt, M.A., Kemp, B., Soede, N.M., 2011a. Effects of altrenogest treatments before and after weaning on follicular
development, farrowing rate, and litter size in sows. J. Anim. Sci. 89, 2397–2406.
van Leeuwen, J.J., Williams, S.I., Martens, M.R., Jourquin, J., Driancourt, M.A., Kemp, B., Soede, N.M., 2011b. The effect of different postweaning altrenogest
treatments of primiparous sows on follicular development, pregnancy rates, and litter sizes. J. Anim. Sci. 89, 397–403.
Varley, M.A., 1983. The regulation of oestrous cycles in groups of post-pubertal female pigs using allyl-trenbolone. Anim. Sci. 2, 211–215.
Werlang, R.F., Argenti, L.E., Fries, H.C., Bernardi, M.L., Wentz, I., Bortolozzo, F.P., 2011. Effects of breeding at the second oestrus or after post-weaning hormonal
treatment with altrenogest on subsequent reproductive performance of primiparous sows. Reprod. Domest. Anim. 46, 818–823.
Wood, C.M., Kornegay, E.T., Shipley, C.F., 1992. Efficacy of altrenogest in synchronizing estrus in two swine breeding programs and effects on subsequent re-
productive performance of sows. J. Anim. Sci. 70, 1357–1364.
Yan, L., Robinson, R., Shi, Z., Mann, G., 2016. Efficacy of progesterone supplementation during early pregnancy in cows: a meta-analysis. Theriogenology 85,
1390–1398.
Zak, L.J., Cosgrove, J.R., Aherne, F.X., Foxcroft, G.R., 1997. Pattern of feed intake and associated metabolic and endocrine changes differentially affect postweaning
fertility in primiparous lactating sows. J. Anim. Sci. 75, 208–216.

12