Scholarly article on topic 'Triggering ovulation with gonadotropin-releasing hormone agonist versus human chorionic gonadotropin in polycystic ovarian syndrome. A randomized trial'

Triggering ovulation with gonadotropin-releasing hormone agonist versus human chorionic gonadotropin in polycystic ovarian syndrome. A randomized trial Academic research paper on "Clinical medicine"

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{"Gonadotropin-releasing hormone (GnRH) agonist" / "Human chorionic gonadotropin (hCG)" / "Polycystic ovarian syndrome (PCOS)"}

Abstract of research paper on Clinical medicine, author of scientific article — Amr Hassaan Farag, Mohamed Hassan Nasr El-deen, Rasha Mostafa Hassan

Abstract Objectives: To compare GnRH agonist to hCG for triggering ovulation in polycystic ovarian syndrome treated with clomiphene citrate. Study design: Prospective randomized study. Materials & methods: Eighty five infertile women with PCOS participated in a randomized allocation concealed prospective trial and had induction of ovulation with clomiphene citrate. GnRH agonist 0.2mg subcutaneously (group 1) or hCG 10,000 IU intramuscularly (group 2) was given to trigger ovulation. Primary outcome was mid-luteal serum progesterone, while secondary outcomes were ovulation rates and clinical pregnancy rates along 3 cycles. Results: No difference was found between group 1 and group 2 regarding mean serum progesterone and clinical pregnancy rates in each cycle. Cumulative pregnancy rates were similar (17.14% versus 20% respectively; P =0.332). Ovulation rates were 80% versus 68.6% (P =0.413); 94.3% versus 90.9% (P =0.669); 97.1% versus 93.7% (P =0.603) in the two groups respectively. However, a significant rise in number of patients with mid-luteal serum progesterone >10ng/mL was noted in the 3rd cycle between both groups, (P <0.0001 for group 1 while P =0.007 for group 2). Conclusion: Triggering ovulation with GnRH-a after treatment with clomiphene citrate in PCOS, in view of its known protective effect against OHSS, may be an effective physiological alternative to conventional hCG without compromising luteal function and pregnancy rates after repeated cycles of treatment.

Academic research paper on topic "Triggering ovulation with gonadotropin-releasing hormone agonist versus human chorionic gonadotropin in polycystic ovarian syndrome. A randomized trial"

Middle East Fertility Society Journal (2015) xxx, xxx-xxx

Middle East Fertility Society Middle East Fertility Society Journal

www.mefsjournal.org www.sciencedirect.com

ORIGINAL ARTICLE

Triggering ovulation with gonadotropin-releasing hormone agonist versus human chorionic gonadotropin in polycystic ovarian syndrome. A randomized trial

Amr Hassaan Farag Mohamed Hassan Nasr El-deen a, Rasha Mostafa Hassan b

Obstetrics and Gynaecology department, Ain Shams University, Abbasia Square, Cairo, Egypt Assiut University, Assiut, Egypt

Received 17 November 2014; accepted 25 January 2015

KEYWORDS

Gonadotropin-releasing hormone (GnRH) agonist; Human chorionic gonado-tropin (hCG);

Polycystic ovarian syndrome (PCOS)

Abstract Objectives: To compare GnRH agonist to hCG for triggering ovulation in polycystic ovarian syndrome treated with clomiphene citrate. Study design: Prospective randomized study. Materials & methods: Eighty five infertile women with PCOS participated in a randomized allocation concealed prospective trial and had induction of ovulation with clomiphene citrate. GnRH agonist 0.2 mg subcutaneously (group 1) or hCG 10,000 IU intramuscularly (group 2) was given to trigger ovulation. Primary outcome was mid-luteal serum progesterone, while secondary outcomes were ovulation rates and clinical pregnancy rates along 3 cycles. Results: No difference was found between group 1 and group 2 regarding mean serum progesterone and clinical pregnancy rates in each cycle. Cumulative pregnancy rates were similar (17.14% versus 20% respectively; P = 0.332). Ovulation rates were 80% versus 68.6% (P = 0.413); 94.3% versus 90.9% (P = 0.669); 97.1% versus 93.7% (P = 0.603) in the two groups respectively. However, a significant rise in number of patients with mid-luteal serum progesterone >10 ng/mL was noted in the 3rd cycle between both groups, (P < 0.0001 for group 1 while P = 0.007 for group 2). Conclusion: Triggering ovulation with GnRH-a after treatment with clomiphene citrate in PCOS, in view of its known protective effect against OHSS, may be an effective physiological alternative

Corresponding author at: 22 Sharpe Close, Warwick, Warwickshire CV34 5BY, UK. Tel.: +44 7557763797.

E-mail addresses: dr_amrhassaan@hotmail.com (A.H. Farag),

Hassanmo2000@yahoo.com (M.H.N. El-deen).

Peer review under responsibility of Middle East Fertility Society.

http://dx.doi.org/10.1016/j.mefs.2015.01.002

1110-5690 © 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

to conventional hCG without compromising luteal function and pregnancy rates after repeated cycles of treatment.

© 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Gonadotropin-releasing hormone agonist (GnRH-a) has been used to suppress gonadotropins in several conditions including endometriosis, uterine fibroids, central gonadotro-pin-dependent precocious puberty (1), where gonadotropin suppression does not occur immediately, but there is a transient increase "flare" in sex hormone levels, followed by a lasting suppression of hormone synthesis and secretion (2).

When using GnRH analogues to trigger ovulation, the mean concentration of LH as measured by radioimmunoassay may be actually raised although there is reduced pulsatile secretion and so the bioactive LH is markedly reduced (3,4), where the GnRH-a induced surge consists of two phases; a short ascending one (4 h) and a long descending one (20 h), with subsequent induction of an FSH surge comparable with the surge of the natural cycle (5).

Kol and Itskovitz-Eldor stated that when using GnRH-a to trigger ovulation in IVF cycles, the LH surge is associated with a rapid rise of progesterone and the attainment of peak E2 levels through the first 12 h after GnRH-a administration which is followed by a temporary suppression of progesterone biosynthesis and a gradual drop in E2 levels during the 24 h before follicle aspiration. After oocyte retrieval, a second rise in progesterone and continuous fall in E2 are noted, reflecting transitions from follicular to luteal phase in ovarian steroido-genesis (6).

A single dose of GnRH-a is able to trigger a pre-ovulatory LH/FSH surge, leading to oocyte maturation in women undergoing ovarian stimulation for IVF or induction of ovulation in vivo while luteolytic effect induced by GnRH analogue trigger, has a protective effect against development of ovarian hyper-stimulation (7). Results of a recent metanalysis suggested that the results of using GnRH agonist and hCG were comparable regarding the numbers of oocytes capable of being fertilized and undergoing embryonic cleavage (8). Also, incidence of empty follicle syndrome was found to be similar in a retrospective study (9). A recent international retrospective analysis of 275 IVF cycles showed a pregnancy rate of 41.8% per cycle and 0.72% risk of severe OHSS after triggering ovulation with GnRH followed by luteal support (10). On the other hand, Youssef et al. in their systematic review of 11 RCT's concluded that GnRH triggering had a negative effect on pregnancy and live birth rates in fresh autologous IVF/ICSI cycles but certainly reduced the risk of OHSS (11).

This study was designed to find out whether triggering ovulation with GnRH agonist compared to hCG in patients with PCOS in non-IVF cycles and in the absence of luteal support, would provide a difference as regards ovulation rates, mid-luteal serum progesterone levels and clinical pregnancy rates.

2. Materials and methods

This randomized, allocation-concealed, prospective study was conducted in Maternity and Children Hospital in Assiut and Assiut University Maternity hospital, Egypt, during the period from November 2010 to August 2012 after being approved by the local institutional ethics and research committee, where 137 infertile women with PCOS were initially enrolled to participate in the study (Fig. 1) where women were considered eligible if having two or all of the following: Oligo- or anovu-lation manifested by menstrual irregularities especially, oligomenorrhea which was defined as cycle duration between 35 days and six months (12), polycystic ovary morphology on trans-vaginal ultrasound scan done by expert radiologist, with the presence of 12 or more follicles in either or both ovaries measuring 2-9 mm in diameter, and/or increased ovarian volume >10 mL (13) and clinical or biochemical evidence of hyper-androgenism in the form of acne or hirsutism using modified Ferriman-Gallwey scoring system (14). Presence of one of the followings was considered sufficient to exclude women from enrollment to the study: male or other female factors of infertility, past history of abdomino-pelvic surgery, medical or endocrinal disorders that can affect fertility as hyper-prolactinemia, thyroid diseases or endometriosis. Forty three patients were excluded due to the presence of male factor, tubal factor, hyper-prolactinemia or hypothyroidism. Nine eligible patients declined participation in the study while eighty-five patients accepted and an informed consent was obtained then they had induction of ovulation starting from day 3 of the cycle with Clomid® 50 mg, Aventis Pharma Limited, UK, two tablets daily for 5 successive days followed by fol-liculometry using vaginal 4.5 MHz endocavity transducer and Sonoace® 8800 digital gaia system, starting at day 10 of the cycle till leading follicle reached 18-22 mm in diameter. Endometrial thickness was measured at the time of follicular maturation and ensured being p 7 mm (15). Participants were randomized into two groups using a computer-generated sequence and the randomization list was held in a secure box and the participants were assigned to their groups using sequentially-numbered opaque sealed envelopes that were opened at the start of study. Women assigned to Group 1, received single dose triptorelin (Decapeptyl® 0.1 mg/mL pre-filled syringe, Ferring, Switzerland) 2 syringes (0.2 mg) subcu-taneously, while women assigned to Group 2, received single dose hCG (Choriomon® 5000 IU vials, IBSA, Switzerland) 2 vials (10,000 IU) intramuscularly. The injections were given at follicular maturation and instructions were given for planned intercourse within the following 36 h which was confirmed by patients on next visit to obtain blood samples. 2 mL of blood samples was taken for serum progesterone assay 7 days after ovulation trigger and the samples were collected in dry tubes then centrifuged and serum stored at 2-8 0C until hormonal assay by enzyme immunoassay and fluorescent

ARTICLE IN PRESS

Gonadotropin-releasing hormone agonist for triggering ovulation in polycystic ovarian syndrome 3

Enrolment

Assessed for eligibility (n=137) Infertile couple where women diagnosed with PCOS during the study period

Excluded (n=43)

■ Diagnosed male factor by semen analysis

(n=21)

■ Tubal factor detected by HSG (n=7)

■ Diagnosed hyperprolactinaemia (n=9)

■ Diagnosed hypothyroidism (n=6)

Eligible women (n=94)

Excluded (n=9) > ■ Declined to participate

Allocation

Received Triptorelin (n=43) Received Choriomon (n=42)

Analysis |

Analyzed (n= 35) ■ Excluded from analysis (Clomiphene resistant or endometrium<7mm; n=8) Analyzed (n= 35) ■ Excluded from analysis (Clomiphene resistant or endometrium<7mm; n=7)

Figure 1 Participants' flow diagram.

detection. If a period was missed for a week, ß-hCG was tested in blood samples using immunoassay and pregnant women were followed up by abdominal ultrasound scan at 6 weeks from the date of first day of last menstrual period, using 2D convex abdominal probe 4-9 MHz to confirm clinical pregnancy. If pregnancy did not occur, the patient was followed up for 2 more successive cycles with the same procedure. Women resistant to clomiphene induction with failure to reach follicle maturation, were not analyzed in the study (15 participants).

The primary outcome measured was mid-luteal serum progesterone level, while secondary outcomes were ovulation rates and clinical pregnancy rates in the two groups along the three cycles of treatment.

Sample size calculation was performed by G Power® version 3.1.5 computer software [Franz Faul, Universität Kiel, Germany]. It revealed that at least 35 patients were needed in each group for detection of a difference in mid-luteal serum progesterone level of at least 3 ng/mL, assuming its mean and standard deviation level in the third cycle is about 10 ng/mL and 3.8 ng/mL respectively (effect size is 0.79) with a power of 0.9 and significance level (a error) of 0.05 (16).

2.1. Statistical analysis

Statistical analysis was done on a personal computer using IBM® SPSS® Statistics version 19 (IBM® Corporation, Armonk, NY, USA). Kolmogorov-Smirnov test of normality was applied to all measured variables where quantitative variables were described as mean and standard deviation (SD) versus median and inter-quartile range (IQR) as appropriate. The qualitative variables were described as number and percentage (%). Chi-square test was used to compare qualitative variables between groups while, independent sample t-test was used to compare two groups as regards quantitative variables in parametric data, Mann Whitney U test was used to compare quantitative non-parametric variables, and paired samples t-test was used to compare first and last cycle results within the same group. P < 0.05 was considered as statistically significant.

3. Results

Statistical analysis included 70 patients; 35 in Group 1 and 35 in Group 2. Table 1 shows no significant difference between

Table 1 Comparison between groups as regards data at the start of the study.

Studied parameters Studied groups P value

Group 1 Group 2

(Triptorelin) (hCG)

(n = 35) (n = 35)

Participant's age (years), mean ± SD 26.94 ± 4.24 26.80 ± 4.20 0.89

Body mass index (kg/m2), mean ± SD 28.52 ± 2.03 29.28 ± 2.17 0.135

Basal day 3 LH level (mIU/mL), mean ± SD 9.17 ± 1.47 9.80 ± 2.48 0.201

Oligo/amenorrhea, n(%) 23(65.7%) 24(68.6%) 1.00

Primary infertility, n(%) 30(85.7%) 28(80.0%) 0.752

Secondary infertility, n(%) 5(14.3%) 7(20.0%)

Clinical hyperandrogenism, n(%) 35(100%) 31(88.5%) 0.114

hCG, Human chorionic gonadotropin; LH, luteinizing hormone; kg/m2, kilograms per meter squared; mIU/mL, milli-international units per

milliliter; SD, standard deviation.

Analysis using independent Student's t-test or Chi-square test as appropriate.

Table 2 Comparison between groups as regards outcomes of

the study.

Studied parameters Studied groups P value

Group 1 Group 2

(Triptorelin) (hCG)

(n = 35) (n = 35)

Clinical pregnancy n(°%)

After 1st cycle 0(0%) 2(5.7%) 0.493

After 2nd cycle 0(0%) 1(3%) 0.485

After 3rd cycle 6(l7.1%) 4(12.5%) 0.736

Mid-luteal P (ng/mL), mean ± SD

After 1st cycle 7.25 ± 4.52 7.25 ± 4.52 0.880

After 2nd cycle 10.68 ± 4.45 10.85 ± 4.59 0.877

After 3rd cycle 12.34 ± 3.43 11.05 ± 4.20 0.166

P value <0.000^ 0.007t

hCG, Human chorionic gonadotropin; P, progesterone.

Analysis using independent Student's t-test or paired samples t-test

or Chi-square test as appropriate.

^ Statistical significance.

Table 3 Comparison between groups as regards ranges of

mid-luteal serum progesterone level during 3 cycles of

induction.

Studied parameters Studied groups P value

Group 1 Group 2

(Triptorelin) (hCG)

(n = 35) (n = 35)

First cycle mid-luteal progesterone

<3 ng/mL, n(%) 7(20%) 11(31.4%) 0.39

3-10 ng/mL, n(%) 19(54.3%) 13(37.1%) 0.37

>10 ng/mL, n(%) 9(25.7%) 11(31.4%) 0.69

Second cycle mid-luteal progesterone

<3 ng/mL, n(%) 2(5.7%) 3(9.1%) 0.62

3-10 ng/mL, n(%) 11(31.4%) 9(27.3%) 0.78

>10 ng/mL, n(%) 22(62.9%) 21(63.6%) (n = = 33) 1.00

Third cycle mid-luteal progesterone

<3 ng/mL, n(%) 1(2.9%) 2(6.3%) 0.52

3-10 ng/mL, n(%) 4(11.4%) 9(28.1%) 0.16

>10 ng/mL, n(%) 30(85.7%) 21(65.6%) (n = 32) 0.48

hCG, Human chorionic gonadotropin; ng/mL, nanograms per

milliliter.

Analysis using Chi-square test.

both groups regarding mean age, BMI, day 3 serum LH level, presence of oligo/amenorrhea, presence of anovulation, primary or secondary infertility and clinical hyper-androgenism (P > 0.05).

Table 2 illustrates studied outcomes showing no significant difference between both groups regarding mean serum progesterone and clinical pregnancy rates in each cycle of induction (P > 0.05). The number of mature follicles as detected by the ultrasound scan did not show significant difference between group 1 and group 2 (median: 2, 2 respectively; P = 0.83). Also, the cumulative pregnancy rate was similar between the two groups after the three cycles where 6 patients of the triptorelin group got pregnant with a cumulative rate of 17.14% while 7 patients in the hCG group got pregnant with a cumulative rate of 20% (P = 0.332).

Table 3 shows no significant difference between both groups regarding number of patients with mid-luteal serum progesterone < 3 ng/mL, 3-10 ng/mL and >10 ng/mL in all the three cycles of treatment (P < 0.05). Also, ovulation rates (serum progesterone P3 ng/mL) for the cycles were 80%

versus 68.6% (P = 0.413); 94.3% versus 90.9% (P = 0.669); 97.1% versus 93.7% (P = 0.603) in the two groups respectively. However, a significant rise in number of patients with mid-luteal serum progesterone >10 ng/mL was noted in the 3rd cycle between both groups, (P < 0.0001 for triptorelin group while P = 0.007 for hCG group).

4. Discussion

Although the role of GnRH-a in triggering ovulation has been investigated in many trials before (5,8,10,17-32), most of these trials had heterogenous populations and mainly focused on patients receiving GnRH antagonist protocol prior to IVF/ ICSI and interventions with variable doses tested. Also, conflicting results have been obtained (Table 4). Moreover, most studies used luteal phase support which clearly affected the outcomes.

ia , et

Table 4 Summary of previous trials comparing GnRH-a to hCG for ovulation triggering.

Authors

Study type

Population

Intervention(s)

Luteal support

Results

Segal and Casper (1992) Lanzone et al. (17) Scott et al. (18)

Shalev et al. (20) Humaidan et al. (З0)

Kolibianakis et al. (2З)

Babayof et al. (22) Pirard et al. (ЗЗ)

Humaidan et al. (25)

Engmann et al. (З4)

Melo et al. (З5) Sismanoglu et al. (З6)

Schmidt-Sarosi et al. (19) RCT

IVF patients n = PCOS patients n

ЗЗ (40 cycles)

RCT (cross-controlled)

Ovulatory patients (unexplained or male factor) n =

Infertile women n = 26

RCT RCT

RCT RCT

Retro-spective RCT

RCT (cross-controlled)

Anovulatory patients n = 210 IVF patients n =122

IVF patients n = 106

PCO patients undergoing IVF n = 28 IVF/ICSI patients n = 23

Normogonadotrophic IVF/ICSI patients n = 45

Patients with PCOS during IVF

cycles

Oocyte donation IVF cycles n = 100

Oocyte donation IVF cycles n = 44 (88 cycles)

COH then LA 500 mcg SC versus hCG 5000 IU IM

COH by Gn. 5000 IU IM hCG or 200 mcg SC GnRH-a

100 mg CC then 2 mg SC LA in one cycle and 10,000 IU IM hCG in another cycle followed by IUI 50 mg CC then 400 mcg nafarelin IN versus IM 5000 IU hCG. On LD6, 7 more 400 mcg doses of nafarelin every 16 h or a single 2500 IU dose of hCG

CC then 0.1 mg triptorelin SC or 10,000 IU hCG IM COH GnRH antagonist/recombinant FSH then Buserelin 0.5 mg SC or hCG 10,000 IU IM

COH GnRH antagonist/recombinant FSH then triptorelin 0.2 mg SC or hCG 10,000 IU IM COH GnRH antagonist/recombinant FSH then GnRH-a or hCG COH hMG/FSH and GnRH antagonist then hCG 10,000 IU IM or IN Nafarelin 100 mcg tds COH Gn/GnRH antagonist then hCG 10,000 IU IM or Buserelin 0.5 mg SC + hCG 1500 IU IM 35 h after

GnRH antagonist then GnRH-a for trigger (study) versus OCP and GnRHa overlap then hCG for triggering (control) COH then triptorelin 0.2 mg SC versus 250 mcg recombinant hCG IM

COH with GnRH antagonist protocol then 0.15 mg SC LA versus hCG

Vaginal P P for subgroup None

Oral E2 and vaginal P

Oral E2 and vaginal P

Vaginal P Vaginal P

Vaginal P

IM P ( + E2 patches for study group)

Vaginal P Vaginal P

Similar pregnancy rates. Lower luteal E2 and P in LA

Similar ovulation and pregnancy rate. Lower mid-luteal P in GnRH-a Mid-luteal serum P higher with hCG. Similar ovulation and pregnancy rates

Similar mid-luteal P, luteal phase length and pregnancy rates

Similar mid-luteal progesterone, pregnancy and abortion rates More M2 oocytes but less implantation and pregnancy rates, P level and more early pregnancy loss with Buserelin

Less pregnancy rates with triptorelin, study discontinued

Comparable pregnancy rates, less P levels and less OHSS with GnRH-a Comparable pregnancy rates and luteal P levels

Comparable P levels and pregnancy rates

Similar oocytes outcome, implantation rate, clinical pregnancy rate and delivery rate

Similar number of oocytes and IVF outcome with less OHSS in triptorelin group

Similar fertilization, implantation and pregnancy rates. Lower OHSS with LA

RCT, randomized controlled trial; IVF, in-vitro fertilization; COH, controlled ovarian hyper-stimulation; LA, leuprolide acetate; mcg, micrograms; SC, subcutaneous; hCG, human chorionic gonadotropin; IU, international units; IM, intra-muscular; P, progesterone; E2, estradiol; PCOS, polycystic ovary syndrome; Gn, gonadotropins; GnRH-a, Gonadotropin releasing hormone agonist; mg, milligrams; CC, clomiphene citrate; IUI, intra-uterine insemination; IN, intra-nasal; LD, luteal day; h, hours; FSH, Follicle stimulating hormone; M2, metaphase 2; ICSI, intra-cytoplasmic sperm injection; hMG, human menopausal gonadotropins; tds, ter die sumendum (3 times a day); OCP, oral contraceptive pills; OHSS, ovarian hyper-stimulation syndrome.

Clomiphene citrate remains the first-line treatment for ovulation induction in non-IVF cycles in patients with PCOS. Thus in the current study, clomiphene citrate was used for ovulation induction in patients with PCOS not only for being effective in such group but also for its remote risk of OHSS.

In the current study, 6 patients of the triptorelin group got pregnant after the three cycles with a cumulative rate of 17.14% while 7 patients in the hCG group got pregnant with a cumulative rate of 20%. The difference was not significant. Other studies on non-IVF cycles found similar pregnancy rates for hCG and GnRH agonist although Lanzone et al., used gonadotropins for ovarian stimulation and supplied a subgroup with progesterone for luteal support (17) and Scott et al. used 2 mg leuprolide acetate in ovulating patients having super-ovulation before IUI (18) while Schmidt-Sarosi et al., used repeated intranasal nafarelin doses (19) and Shalev et al., used a smaller dose (0.1 mg) of triptorelin (20). Some of the above studies found no difference in mid-luteal serum progesterone between GnRH-a and hCG groups (19,20), while others found lower levels in GnRH-a group (17,18) but such differences could be related to smaller number of participants in these studies as well as different populations and interventions.

The effect of GnRH-a on luteal function has been contradictory through previous studies. Although it may improve luteal function through peri-ovulatory FSH surge by inducing LH receptor formation in the luteinizing granulosa cells as well as promoting oocyte maturation and cumulus expansion (5), it has been found on the other hand to adversely affect follicular fluid hormones especially progesterone (30), as well as decreasing serum inhibin A (21,22) and pro-alphaC levels (21). Nevertheless, Kolibianakis et al., have stopped their study for very low pregnancy rates with GnRH-a (23).

In view of the above findings, it was thought that luteal support is necessary with GnRH-a trigger (5,24) hence, Humaidan et al. suggested a rescue dose of 1500 IU hCG for luteal support (25) which resulted in high pregnancy and live birth rates (26,27), also Kol et al. suggested 2 doses of 1500 IU hCG (28). Lin et al., have studied dual triggering with GnRH-a and hCG and found it to be superior to hCG triggering regarding implantation, pregnancy and live birth rates in IVF cycles induced with GnRH antagonist (29).

The use of clomiphene citrate with its long half-life in ovulation induction during the follicular phase is associated with a higher pituitary secretion of LH during the luteal phase that can counteract the luteolytic action following the GnRH agonist trigger (28). Furthermore, retrieval of more mature oocytes in the GnRH agonist triggered group seen in other studies, supports the possible beneficial effect of the mid-cycle FSH surge on oocyte maturation (30). During the current study, a total of seven patients developed mild OHSS while no patients had moderate/severe OHSS. Moreover, the 13 pregnancies reported were all clinical not only chemical pregnancies.

For the best of the authors' knowledge, the use of GnRH-a in triggering ovulation was mainly tested before in IVF patients receiving GnRH antagonist for ovarian stimulation and the main outcome was decreasing the risk of OHSS while in the current study, the effect on the luteal function was the main outcome on a population of PCOS patients receiving clomiphene citrate for ovulation induction and followed by timed natural intercourse without the use of

luteal support. Also, the study uniquely studied repeated cycles of treatment which showed increase in ovulation rates in both groups, hence the authors believe that triggering ovulation with GnRH-a after treatment with clomiphene citrate in PCOS, besides its known protective effect against OHSS, may be an effective alternative to conventional hCG without compromising luteal function and pregnancy rates after repeated cycles of treatment.

The limitation of this study is that it did not follow up pregnant patients for the detection of ongoing pregnancies and live birth rates. Also, the hypothesis that GnRH-a, being more physiological in PCOS, confronted similar success rates between both groups and so, treatment cost should be considered. Moreover, more studies on larger numbers of patients are needed to confirm the effect of GnRH-a on lowering basal LH levels in PCOS and correlate this effect to other biochemical markers.

Conflict of Interest

No actual or potential conflict of interest in relation to this manuscript exists.

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