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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 2  |  Page : 387-391

Ovulation triggers in infertility


1 Department of Obstetrics and Gynecology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Obstetrics and Gynecology Department at Berket El Sabaa General Hospital, Ministry of Health, Berket El Sabaa, Menoufia, Egypt

Date of Submission21-Apr-2019
Date of Decision04-Jun-2019
Date of Acceptance17-Jun-2019
Date of Web Publication27-Jun-2020

Correspondence Address:
Heba T M El-Rakhawy
Berket El Sabaa, Menoufia 32651
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_158_19

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  Abstract 

Objective
To compare the effect of oxytocin (OXT) versus human chorionic gonadotropin (HCG) versus combination of both on ovulation triggering.
Background
HCG has been used as an alternative to luteinizing hormone for triggering ovulation. HCG has high cost and needs close monitoring. In this study, we try to clarify the possible role of OXT as an alternative to HCG for triggering ovulation.
Patients and methods
A randomized controlled clinical trial was carried out on 108 infertile women with anovulation or oligo-ovulation; each of them received 100-mg clomiphene citrate from the second to the sixth day of the cycle and were monitored by transvaginal sonography. They were randomly divided into four groups: group 1 received 10 000 IU HCG, group 2 received 10 IU OXT, group 3 received both of them, and group 4 did not receive any triggering medication.
Results
There was significant difference regarding ovulation between studied groups and control (33.3%). There was no significant difference in ovulation between HCG group versus OXT group (χ2 = 0.83,P= 0.362), HCG group versus combination group (χ2 = 0.11,P= 0.735) and OXT group versus combination group (χ2 = 1.54,P= 0.214). There were statistically significant high plasma progesterone levels between studied groups and control (P = 0.001). There was significant difference in pain sensation between HCG group versus OXT and combination groups (P = 0.001).
Conclusion
OXT is suggested to be used alone or in combination with HCG for triggering ovulation.

Keywords: clomiphene citrate, human chorionic gonadotropin, infertility, ovulation induction, oxytocin


How to cite this article:
Saleh SA, Aboali HA, El-Rakhawy HT. Ovulation triggers in infertility. Menoufia Med J 2020;33:387-91

How to cite this URL:
Saleh SA, Aboali HA, El-Rakhawy HT. Ovulation triggers in infertility. Menoufia Med J [serial online] 2020 [cited 2020 Oct 28];33:387-91. Available from: http://www.mmj.eg.net/text.asp?2020/33/2/387/287749




  Introduction Top


Infertility is failure to establish a clinical pregnancy after 12 months of regular and unprotected sexual intercourse[1]. Ovulation induction is the use of medication to stimulate normal ovulation in women with ovarian dysfunction[2]. Several medical options are available to treat ovulation disorders and infertility. It is difficult to identify the most effective treatment based on direct evidence[3]. human chorionic gonadotropin (HCG) in combination with clomiphene citrate (CC) has been used as an alternative to luteinizing hormone (LH) for ovulation induction[4]. This procedure is considered as a standard method for inducing final stages of oocyte maturation[5]. HCG is an expensive drug that needs monitoring[6]. Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of assisted reproduction technology, and its occurrence is dependent on the administration of HCG[7]. Several studies have been conducted to clarify the role of oxytocin (OXT) in the central and peripheral tissues such as uterus, placenta, amniotic sac, corpus luteum, testes, and heart[8]. OXT, in addition to its contraction stimulating property, acts as a regulator of gonadotropin-releasing hormone and LH release[9]. On the contrary, administration of OXT antagonist resulted in decreasing of LH concentration. OXT has stimulatory effects on steroidogenesis, ovulation, and endometrial luteinization. It promotes several different mechanisms on reproductive system[10]. OXT has stimulatory effects on estradiol (E2) and progesterone (P) secretion; therefore, OXT chronologically correlates with a rise in the level of estrogen at mid cycle[11]. Several studies have been conducted to clarify the role of OXT as an ovulation trigger. However, the mechanism of regulation, timing, and initiation of ovulation is still controversial[11]. OXT hormone has receptors on endometrial, granulosa, cumulus, and luteal cells. Presence of OXT receptor mRNA in granulosa cells before ovulation shows that OXT may be involved in the development of the follicle and induction of ovulation[9]. OXT can regulate ovulation, increase LH androgen, induce final stages of oocyte maturation, and facilitate follicle rupture[4],[11].

The aim of this study was to compare the effect of OXT versus HCG versus combination of both as an ovulation trigger.


  Patients and Methods Top


This randomized controlled study was carried out on 108 infertile women fulfilling the criteria of the study selected among those who came to the clinics of Menoufia University Hospital and Berket El Sabaa General Hospital from the period from July 2017 till January 2019 after approval of the study by institute ethical committee. Informed consent from the patients was obtained. Oligo or anovulation patients belong to WHO group II hypothalamic–pituitary–ovarian axis dysfunction. They were diagnosed by history, serial folliculometry, and multiple serum progesterone levels, which were less than 3 ng/dl all over the cycle. Inclusion criteria include infertile women with oligo or anovulation, under 40 years old, and with patent tubes on hysterosalpingography. Exclusion criteria include abnormal recent semenogram, uterine abnormalities, abnormal physical exam, CC resistance, taking any drug affecting ovulation, hyperprolactinemia, hypersensitivity to OXT, and a history of cardiovascular disease. Each of them received 100-mg CC from the second to the sixth day of one cycle and were monitored by transvaginal sonography in the same cycle. In case of presence of a follicle with a diameter larger than 18 mm, they were randomly divided into four groups: group 1 received 10 000 IU HCG (Epifasi 5000 IU ampoule; EIPICO, Tenth of Ramadan City - 1st Industrial Zone B1, Egypt), group 2 received 10 IU OXT (Syntocinon 10 IU ampoule; Novartis, Cairo &Guiza Scientific Office, 7 El-Khalily St., Hesny building - Area 1147, Sheraton, Heliopolis – Cairo), group 3 received 10 IU OXT and 10 000 IU HCG, and group 4 did not receive any ovulation triggers. They received saline solution as a placebo. Ovulation was confirmed 1 week after injection by serum progesterone level more than 3 ng/ml, sonographic evidence of corpus luteum, or fluid in cul de sac. Primary outcome measures are occurrence of ovulation and level of progesterone. Secondary outcome measures are number and diameter of follicles, endometrial thickness (ET), OHSS and ovarian cyst formation, and occurrence of pregnancy. A plan of work was sealed in closed envelops and numbered. Packing, sealing, and numbering were performed by independent doctors. Randomization coding tables were concealed till the end of the study. There was double blindness. We were not aware whether patients received HCG, OXT, both of them, or a placebo as an ovulation trigger.

Statistical analysis: data were collected and analyzed using SPSS program version 20 (SPSS Inc., Chicago, Illinois, USA). Numerical variables reported as mean ± SD, and qualitative variables reported as frequency and frequency percentage. Suitable statistical tests [Mann–Whitney test, one-way analysis of variance (F test), Kruskal–Wallis test, post-hoc test, and χ2] were used according to the data type. P value was considered significant when up to 0.05.


  Results Top


There is no significant difference between the study groups regarding age, BMI, and infertility duration. ET showed significant difference between HCG group versus control and combination group versus control, but no significant difference between HCG versus OXT groups, HCG versus combination groups, OXT versus combination group, or OXT versus control (P = 0.037; [Table 1]). Plasma progesterone levels in HCG group, OXT group, combination group, and control were 11.90 ± 16.73, 11.10 ± 8.23, 11.78 ± 6.42, and 5.82 ± 7.21 ng/ml, respectively. There were statistically significant high plasma progesterone levels in HCG, OXT, and combination groups when compared with the control group (P = 0.001), but there was no significant difference in progesterone level between HCG versus OXT group, HCG versus combination group, or OXT group versus combination group [Table 1]. There was no significant difference between the study groups regarding mean follicular size (P = 0.121). It was larger in OXT group (19.38 ± 1.31 mm; [Table 1]). Regarding ovulation, there was significant difference between the studied groups and controls (33.3%), where ovulation was reported more in combination group (81.5%) followed by HCG (77.8%) and then OXT group (66.7%). There was significant difference between HCG group versus control group (χ2 = 10.80, P = 0.001), OXT group versus control (χ2 = 6.0, P = 0.014) and combination group versus controls (χ2 = 12.80, P ≤ 0.001). However, there was no significant difference in ovulation between HCG group versus OXT (χ2 = 0.83, P = 0.362), HCG group versus combination group (χ2 = 0.11, P = 0.735), or OXT group versus combination group (χ2 = 1.54, P = 0.214; [Table 2]). Pain was reported more in OXT (63%) and combination (77.8%) groups than HCG (3.7%) and control groups [Table 2]. There was significant difference in pain sensation between HCG group versus OXT (P < 0.001), HCG versus combination groups (P < 0.001), OXT group versus control (P < 0.001), and combination group versus control (P < 0.001). However, there was no significant difference in pain sensation between HCG versus control (P = 1.0) and OXT versus combination group (P = 0.233; [Table 2]). There was no significant difference between the study groups regarding OHSS, ovarian cyst formation, pregnancy rate or multiple pregnancy percentage (P = 0.206, 0.253, 0.874, and 0.688, respectively; [Table 3]). Regarding hormonal profile, there was no significant difference in the levels of LH (P = 0.198 mlU/ml), E2 (P = 0.135 pg/ml), prolactin (P = 0.773 ng/ml), and thyroid stimulating hormone (P = 0.530 mU/l) among the studied groups. Follicular stimulating hormone levels were significant higher in HCG (6.30 ± 0.83 mlU/ml) and combination groups (6.21 ± 1.03 mlU/ml) versus control (5.52 ± 0.93 mlU/ml), but with no significant difference between HCG and OXT groups [Table 4].
Table 1: Distribution of the studied groups regarding endometrial thickness and progesterone level and follicular size

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Table 2: Distribution of the studied groups regarding pain and ovulation

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Table 3: Distribution of the studied groups regarding the treatment sequences and results

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Table 4: Distribution of the studied groups regarding their hormonal levels

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  Discussion Top


HCG in combination with CC is considered as a standard method for inducing final stages of oocyte maturation[5]. HCG is expensive and needs monitoring[6]. In this study, we tried to clarify the possible role of OXT as an ovulation trigger. Results of the our study showed statistically significant high plasma progesterone levels in HCG, OXT, and combination groups when compared with control, but there was no significant difference in progesterone level between HCG versus OXT group, HCG versus combination group, and OXT versus combination group. This result was supported by Melli et al.[4], in a study comparing two groups, where the first one received CC plus HCG and the second one received CC plus OXT in two successive cycles, showing that mean level of progesterone in the second cycle was higher in the OXT group. Wadhwa et al.[12] reported that OXT strengthens the effect of factors that stimulate HCG-AMP pathway through cholesterol efflux and inhibition of progesterone metabolism, and OXT does not solely stimulate the synthesis of progesterone but can be involved in regular release of progesterone. Moreover, Mehrotra et al.[13], in a study comparing HCG versus OXT as an ovulation trigger mentioned that plasma progesterone level was not statistically significant higher among OXT group than HCG group[4]. Our results showed no significant difference in ovulation between HCG versus OXT group, HCG versus combination group, and OXT versus combination group. In agreement with this, Melli et al.[4] found no significant differences between HCG and OXT groups in ovulation. Moreover, Mehrotra et al.[13] found statistically nonsignificant difference in ovulation between HCG and OXT groups. Masrour and Azad[5], in a study showing the effect of OXT on ovulation concluded that using CC plus OXT is as efficient as CC plus HCG. OXT can play a role in ovulation either separately or with other ovulatory mechanisms. The stimulatory effect of OXT on ovulation is supported also by Soleimani et al.[8]. ET showed no significant difference between HCG and OXT group, but there was significant difference between HCG versus control and combination versus control group. Biswas et al.[14] found that the mean ET on day of intrauterine insemination (IUI) in group A (ovulation induction with CC and IUI) and group B (ovulation induction with human menopausal gonadotropin and IUI) was higher in human menopausal gonadotropin group compared with CC. It can be explained by antiestrogen effect of CC on the endometrium. There was no significant difference between HCG and OXT groups regarding mean follicular size. It was larger in OXT group. This was in concurrence with the results of Mehrotra et al.[13] and Melli et al.[4]. There was significant difference in pain sensation between HCG versus OXT group, HCG versus combination group, OXT group versus control, and combination group versus control. In agreement with this, Melli et al.[4] found statistically significant difference in pain sensation among OXT group compared with HCG group, but Mehrotra et al.[13] mentioned that difference in pain between HCG group and OXT group did not reach significant values. No significant difference was found between study groups regarding OHSS. In agreement with this result, Melli et al.[4] reported only mild OHSS, with no statistically significant difference, being lower in OXT group. This result was supported by the studies of Mehrotra et al.[13], Masrour and Azad[5], and Javedani et al.[11], as no OHSS was observed in the groups that received either OXT alone or with HCG. However, the mechanism by which OHSS may occurs with HCG was explained by Papanikolaou et al.[15] as HCG facilitate OHSS owing to the sustained luteotropic activity and the production of vascular permeability mediators. These results suggest the role of OXT as an alternative to HCG as an ovulation trigger with no increase in the risk of OHSS. There was no significant difference in ovarian cyst formation between the studied groups. Regarding pregnancy rate, there was no significant increase in pregnancy rate or multiple pregnancy between the study groups. Melli et al.[4], and Mehrotra et al.[13], observed that pregnancy rate is more in OXT group. There was no significant difference in LH, E2, prolactin, or thyroid stimulating hormone level between the studied groups, so there was standardization between all groups in hormonal level to abolish their effect on the results. Follicular stimulating hormone levels were significant higher in HCG and combination groups versus control but with no significant difference between HCG and OXT group.


  Conclusion Top


In women undergoing induction of ovulation, OXT is considered to be an alternative to HCG for triggering of ovulation and could be suggested to be used alone or in combination with HCG.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Masrour MJ, Azad Z. A comparison of the effects of human chorionic gonadotropin and oxytocin on ovulation in PCOS patients from 2015 until 2018. Acta Med Mediterr 2018; 34 :1757–1763.  Back to cited text no. 5
    
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8.
Soleimani RJ, Roshanga L, Nikpoo P. Effect of oxytocin on folliculogenesis and ovulation. Reprod Biomed Online 2008; 16 :36.  Back to cited text no. 8
    
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Roshangar L, Soleimani J, Nikpoo P, Melli MS. Effect of oxytocin injection on folliculogenesis, ovulation and endometrial growth in mice. Iran J Reprod Med 2009; 7 :91–95.  Back to cited text no. 9
    
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Wadhwa L, Khanna R, Gupta T, Gupta S, Arora S, Nandwani S. Evaluation of role of GnRH antagonist in intrauterine insemination (IUI) cycles with mild ovarian hyperstimulation (MOH): a prospective randomised study. J Obstet Gynaecol India 2016; 66 :459–465.  Back to cited text no. 12
    
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Mehrotra S, Singh U, Gupta HP, Tandon I, Saxena P. A prospective double blind study comparing the effects of oxytocin and human chorionic gonadotropin as trigger for ovulation. J Obstet Gynaecol 2014; 34 :13–16.  Back to cited text no. 13
    
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BiswasJK, BandhuHC, SinghH, DeyM. Relation of endometrial thickness and pregnancy rates in intrauterine insemination following ovulation induction. Int J Reprod Contracept Obstet Gynecol 2016; 5 :110–115.  Back to cited text no. 14
    
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Papanikolaou EG, Pozzobon C, Kolibianakis EM, Camus M, Tournaye H, Fatemi HM, et al. Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin-releasing hormone antagonist in vitro fertilization cycles. Fertil Steril 2006; 85 :112–120.  Back to cited text no. 15
    



 
 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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