The Effect of Endometrial Thickness on The Day of Human Chorionic Gonadotropin Injection on Reproductive Outcome in Clomiphene Citrate and Intrauterine Insemination Cycles

doi:10.21203/rs.3.rs-4816375/v1

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Research Article

The Effect of Endometrial Thickness on The Day of Human Chorionic Gonadotropin Injection on Reproductive Outcome in Clomiphene Citrate and Intrauterine Insemination Cycles

https://doi.org/10.21203/rs.3.rs-4816375/v1

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Backround:

To evaluate the effect of endometrial thickness (EMT) on the day of Human Chorionic Gonadtropin(hCG) injection on reproductive outcome in clomiphene citrate and intrauterine insemination cycles (CC + IUI).

Methods

Overall 640 cycles in couples with unexplained infertility or WHO Category 2 normogonadotropic anovulatory women and met the inclusion criteria were analyzed retrospectively. Our study was approved by Ministry of Health, Health Sciences University Etlik Zübeyde Hanim Women’s Institutional Board (30/12/2020-90057706-799) who applied to Reproductive Endocrinology Department of a tertiary center between February 2019 and February 2020 and received ovulation induction with CC + IUI. The demographic characteristics and EMT at the hCG injection day were compared in the group with a clinical pregnancy with those who failed to achieve pregnancy.

Results

Out of the evaluated 640 cycles, 92 cases had a high β-hCG (14.4%) and 80 (12.5%) resulted in a clinical pregnancy. While 23 (23/640, 3.6%) of the cases with clinical pregnancy experienced spontaneous abortion, 52 (8.1%) resulted in live birth. Maternal age, duration of infertility and clomiphene citrate dosage were found to have an impact on the clinical pregnancy and live birth ratio. The cut-off value for endometrial thickness is 8.45 mm (sensitivity 49.4%, specificity 55.3%) for clinical pregnancy. The incidence of biochemical pregnancy was less while the incidence of clinical pregnancy (p = 0.010) and live birth (p = 0.002) was high in cases with an EMT > 8–9 mm on the day of β-HCG injection

Conclusion

Higher pregnancy rates have been reported at certain EMT values. However, cycle success can be predicted not only by EMT but also by considering other factors such as female age, infertility duration, and endometrial pattern.

Endometrial thickness

clinical pregnancy

live birth

clomiphene citrate

insemination

Infertility is defined as failure to achieve pregnancy despite practicing regular sexual intercourse (2 per week) without any contraception for at least 12 months (1). Many of the studies demonstrate that the large majority (80 to 90 percent) of apparently normal couples will conceive within the first year of unprotected regular intercourse. It is also shown that fecundability decreases with the aging of the woman and increased the duration of infertility(2, 3). World Health Organization (WHO) task force on Diagnosis and Treatment of Infertility performed a study on 8500 infertile couples utilizing standard diagnostic criteria and reported female factor infertility in 37%, male factor infertility in 8% of the couples while both male and female factor infertility was present in 35% of the couples in developed countries. Meanwhile, 5% of the couples had unexplained infertility and 15% became pregnant during the study(4).

Clomiphene citrate (CC), an estrogen agonist/antagonist has been widely used for the past 40 years as it is the very first agent used for ovulation induction. CC is used for ovulation induction in combination with intrauterine insemination (IUI) in normogonadotropic anovulatory women and women with unexplained infertility. In the presence of adequate endogenous estrogen levels, CC acts as a competitive estrogen antagonist while it shows estrogenic properties in case of low endogenous estrogen levels. CC binds to nuclear estrogen receptors (ER) in the subthalamic area and thus depletes hypothalamic ERs by blocking the negative feedback effect of circulating endogenous estradiol(E2)(5). This results in stimulation of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency leading to increased serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH)(6). The elevated FSH and LH stimulate ovarian follicular development. CC acts primarily as an anti-estrogen on the uterus, cervix, and vagina and thus the expected normal increase in uterine volume and endometrial thickness(EMT) that occurs during spontaneous menstrual cycles is largely absent during clomiphene-induced cycles, despite the E2 levels being high(7). The use of clomiphene citrate (CC) is associated with the development of a thinner endometrium in 15–50% of patients(8). The thin endometrium is one of the factors blamed for the discrepancy between the ovulation rate and pregnancy rate in CC-induced cycles(9).

The role of the EMT and normal trilaminar appearance evaluated during ultrasonographic examination have been extensively studied in In Vitro Fertilization-Embryo Transfer (IVF-ET) cycles as these parameters have been proposed to be predictors of endometrial receptivity and thus reproductive outcome(10).

In the presented study we aimed to evaluate the effect of EMT on the day of Human Chorionic Gonadotropin (hCG) administration on the reproductive outcomes and determine the threshold value for EMT for achieving clinical pregnancy in CC + IUI cycles.

2.1.Study design

The results of the 640 cycles in couples who received CC + IUI treatment at Reproductive Endocrinology Department of Health Sciences University Etlik Zübeyde Hanım Women’s Training and Research Hospital between February 2019 and February 2020 for unexplained infertility or WHO Category 2 anovulation (normogonadotropic anovulatory women) and met the inclusion criteria were analyzed retrospectively. Our study was approved by the Ministry of Health, Health Sciences University Etlik Zübeyde Hanım Women’s Institutional Board (30/12/2020-90057706-799).

Incompatible with the protocol of the clinic, detailed medical history including age, duration of infertility, medical and gynecological history was taken and recorded during the evaluation of each patient followed by a detailed physical and gynecological examination. Day-3 FSH (Elecsys FSH, Roche), LH (Elecsys LH, Roche), Prolactin (Elecsys Prolactin II, Roche), thyroid-stimulating hormone (TSH) (Elecsys TSH, Roche) levels and Day-21 progesterone (Elecsys Progesterone, Roche) levels are analyzed. Basal transvaginal ultrasonography (TVUSG), basal antral follicle count (AFC), and hysterosalpingography (HSG) were performed as a part of the routine infertility workup. Two sperm samples of the partners were examined after urological examination and the presence of male factor was evaluated according to the WHO criteria(11).

2.2.İnclusion-Exclusion criteria

Women with ovulatory dysfunction (WHO Category 2) or unexplained infertility (ovulatory women with at least one patent tube on HSG and follicular growth on the side of the patent tube and absence of male infertility) were included in the study. Women with the duration of infertility less than a year, bilateral tubal occlusion, a basal FSH ≥ 15mIU/ml, additional endocrine disease (such as Cushing, diabetes, thyroid dysfunction, hyperprolactinemia, androgen-synthesizing tumor, 21-hydroxylase enzyme defect) and who failed to demonstrate follicular growth during the CC treatment cycle or did not receive intrauterine insemination were excluded from the study.

2.3.Treatment Protocol

CC (Klomen®; Kocak Farma / Turkey, Serophene®; Merck Serono / Italy) was commenced on Day-3 and was continued for five days after the onset of spontaneous menses after a TVUSG evaluation. A standard dose of 50 mg/day was used for the first treatment cycle but the treatment doses were increased by 50 mg increments if the patients failed to achieve follicular growth with the given dose during the previous treatment cycle. The maximum CC dose was 150mg/Day according to our protocol. The women were scheduled for IUI 36 hours after subcutaneous hCG injection (250µg recombinant hCG Ovitrelle®; Merck-Serono / Italy) when a follicle reached to a diameter > 17mm. The patients who had more than 3 follicles with a diameter > 17 mm were not scheduled for intrauterine insemination in order to avoid multiple pregnancies and were not included in the study. EMT was measured on the day of hCG injection in the midsagittal plane of the uterus as the maximum distance between the two inner faces of the endometrial myometrial junction and recorded.

The ejaculate was prepared using a swim-up technique. IUI was performed by injecting the prepared semen into the intrauterine cavity using a soft insemination catheter (AINSEBLUE-R RI. MOS. ITALY). Success criteria after IUI was taken as clinical pregnancy(CP). CP was diagnosed with a positive β-hCG (> 10mlU/ml) on the 14th day after IUI followed by observing an intrauterine gestational sac during TVUSG in the 5th week as described by Zhang et al(12). The absence of a gestational sac on TVUSG despite an elevated β-hCG was defined as biochemical pregnancy (13). The findings were compared by comparing the variables of the group with CP with the ones without CP.

2.4.Statistical analysis:

SPSS 21.0 package program was used to analyze the data. Numerical data are mean ± standard deviation, data on categorical variables number (percentage). The compliance of numerical variables to normal distribution was checked by the Shapiro Wilk test. The numerical data conforming to the normal distribution assumption were compared with the independent sample t-test, the numerical data not compatible with the normal distribution assumption with the Mann-Whitney U test, and the categorical variables with the Pearson's Chi-square test. Statistical significance was accepted as p < 0.05.

Out of the 640 cycles evaluated, elevated β-hCG (> 10mlU/ml) was observed in 92 (14.4%). Twelve (1.8%) of these cases were biochemical pregnancies as the β-hCG level declined and a gestational sac was not observed while 80 of the cases (12.5%) achieved clinical pregnancy. Ectopic pregnancy was not observed in the study group. While 23 (23/640, 3.6%) of the cases with CP had spontaneous abortion (SA), 52 (52/640, 8.1%) resulted in live birth (LB) (Table-2). The patients with CP were significantly younger (p = 0.002), the duration of infertility was significantly shorter (p = 0.002), and the CC dosage was statistically significantly higher (p = 0.034) when compared to the group who failed to achieve a CP (Table 1). The age was statistically lower in patients who had an LB (p = 0.018).

Table 1

The demographic characteristics and clinical features of the patient group compared according to the presence of a clinical pregnancy and live birth.
	Clinical Pregnancy			Live Birth		Total (n = 640)
	None (n = 560)	Yes (n = 80)	p	None (n = 588)	Yes (n = 52)		p
Age	28.1 ± 4.99	26.29 ± 4.62	0.002*	28.01 ± 4.95	26.31 ± 5.02	27.88 ± 4.98	0.018*
Infertility type
Primary	387 (69.11%)	55 (68.75%)	0.948	407 (69.22%)	35 (67.31%)	442 (69.06%)	0.775
Secondary	173 (30.89%)	25 (31.25%)		181 (30.78%)	17 (32.69%)	198 (30.94%)
Duration of marriage	4.41 ± 3.3	3.95 ± 3.49	0.245	4.37 ± 3.28	4.17 ± 3.82	4.35 ± 3.33	0.682
Duration of infertility	3.04 ± 1.96	2.44 ± 1.81	0.011*	3 ± 1.94	2.52 ± 2.06	2.96 ± 1.95	0.086
AMH (ng/ml)	4.44 ± 3.1	4.79 ± 3.16	0.368	4.45 ± 3.09	4.83 ± 3.39	4.48 ± 3.11	0.436
FSH (mlU/ml)†	7.07 ± 2.06	6.77 ± 1.83	0.218	7.04 ± 2.06	6.94 ± 1.71	7.03 ± 2.04	0.740
LH (mlU/ml)†	5.71 ± 3.8	6.25 ± 7.19	0.303	5.8 ± 4.46	5.49 ± 3.04	5.78 ± 4.36	0.628
E2 (pg/ml)†	48.3 ± 20.19	46.6 ± 17.01	0.495	48.7 ± 20.13	46.1 ± 14.03	48.1 ± 19.82	0.125
PRL (mg/dl)†	14.09 ± 7.9	14.15 ± 7.97	0.955	14.19 ± 7.96	13.08 ± 7.32	14.1 ± 7.91	0.348
TSH (µg/dl)†	1.98 ± 1.2	2.15 ± 1.26	0.252	1.99 ± 1.22	2.14 ± 1.16	2 ± 1.21	0.375
Body mass index (kg/m²)	24.82 ± 4.33	24.77 ± 5.02	0.920	24.8 ± 4.33	25.02 ± 5.32	24.82 ± 4.42	0.734
Basal USG EMT(mm)	4.61 ± 1.81	4.38 ± 1.61	0.283	4.61 ± 1.79	4.3 ± 1.68	4.59 ± 1.78	0.236
Daily CC dose (mg)	57.23 ± 20.21	62.5 ± 24.52	0.034*	57.48 ± 20.31	62.5 ± 25.96	57.89 ± 20.84	0.180
Ovarian Response
Duration of follicular growth (day)	11.11 ± 2.82	11.75 ± 2.88	0.058	11.11 ± 2.81	12.04 ± 2.92	11.19 ± 2.83	0.024*
Number of Follicle	1.24 ± 0.53	1.11 ± 0.36	0.007*	1.23 ± 0.52	1.1 ± 0.36	1.22 ± 0.51	0.014 *
Diameter of the dominant follicle (mm)	19.34 ± 1.84	19.1 ± 1.68	0.275	19.34 ± 1.85	19 ± 1.36	19.31 ± 1.82	0.203
EMT on the day HCG trigger (mm)	8.47 ± 2.56	8.38 ± 2.16	0.766	8.47 ± 2.55	8.38 ± 2.11	8.46 ± 2.52	0.802
Abbreviations: EMT, Endometrial Thickness; TSH, Thyroid-stimulating hormone; FSH, Follicle-stimulating hormone; LH, Luteinizing hormone; E2, Estradiol; PRL, Prolactin; AMH, Anti-mullerian hormone; CC, Clomiphene citrate; USG, Ultrasonography *P < 0.05 statistically significant †Measurement on the day of the early follicular phase

We compared biochemical pregnancy, CP, SA, and LB. The incremental EMT measurement results were starting to ≤ 6 up to > 15 mm. The rate of clinical pregnancy (CPR), live birth (LBR), and spontaneous abortion (SAR) were evaluated in relation to the endometrial thickness (Table 2).

Table 2

Endometrial Thickness(EMT) on the day of hCG administration
. EMT (mm)	Number of patients (n = 640)	Biochemical Pregnancy (n = 12)	Clinical Pregnancy (n = 80)	Spontaneous Abortion (n = 23)	Live Birth (n = 52)
≤ 6	135	3 (2.22%)	13 (9.63%)	4 (2.96%)	8 (5.93%)
> 6 - ≤7	100	4 (4%)	15 (15%)	5 (5%)	9 (9%)
> 7 - ≤8	113	1 (0.88%)	12 (10.62%)	5 (4.42%)	7 (6.19%)
> 8 - ≤9	111	0 (0%)	22 (19.82%)	3 (2.7%)	17 (15.32%)
> 9 - ≤10	60	2 (3.33%)	6 (10%)	2 (3.33%)	4 (6.67%)
> 10 - ≤11	44	0 (0%)	4 (9.09%)	1 (2.27%)	3 (6.82%)
> 11 - ≤12	2	1 (3.45%)	5 (17.24%)	2 (6.9%)	3 (10.34%)
> 12 - ≤13	23	0 (0%)	2 (8.7%)	1 (4.35%)	0 (0%)
> 13 - ≤14	12	0 (0%)	0 (0%)	0 (0%)	0 (0%)
> 14 - ≤15	8	0 (0%)	1 (12.5%)	0 (0%)	1 (12.5%)
> 15	5	1 (20%)	0 (0%)	0 (0%)	0 (0%)
Distribution of results by endometrial thickness (> 8 & 9) on the day of HCG
8–9mm	111	0 (0%)	22 (19.82%)	3 (2.7%)	17 (15.32%)
< 8.>9 mm	539	12 (2.27%	58 (10.96%)	20 (3.78%)	35 (6.62%)
p	N/A	0.013*	0.010*	0.579	0.002*
Abbrevations: EMT, Endometrial Thickness; HCG, Human Chorionic Gonadotropin. Data are shown as numbers (percentages). *Statistically significant P < 0.05 statistically significant

The mean EMT was found to be 8.38 mm in cases with a CP and the cut-off point for EMT on the day hCG trigger was 8.45 (sensitivity of 49.4.% and specificity of 55.3%) for CP (Figure-1). When we compare the EMT the incidence of biochemical pregnancy was lower (p = 0.013), and CPR (p = 0.010) and LBR (p = 0.002) were higher in cases with an EMT was between 8–9 mm on the day of β-hCG injection. There was no significant difference in the EMT in terms of the incidence of SA (p = 0.579) (Table 2). The distribution of statistically significant data was given in Table 3. Age was found independent factor affecting live birth rates (LBR) according to the multivariant analysis. (Table 4). Decreasing age has a positive effect on the LBR.

Table 3

Distribution of statistically significant data
	Age	Duration of infertility	Daily clomiphene citrate dose (mg)	Number of Follicle	Duration of Follicular growth
Clinical Pregnancy (+) (n = 80)	26.29	2.44	62.5	1.11	11.75
Clinical pregnancy (-) (n = 560)	28.1	3.04	57.23	1.24	11.11
p	0.02*	0.011*	0.034*	0.007*	0.058
Live Birth (+) (n = 52)	26.31	2.52	62.5	1.1	12.04
Live Birth (-) (n = 588)	28.01	3	57.48	1.23	11.11
p	0.018*	0.086	0.180	0.014*	0.024*
Spontaneous abortion (+)(n = 23)	26.57	2.39	65.22	1.09	10.96
Spontaneous abortion(-)(n = 57)	26.31	2.52	62.50	1.10	12.04
p	0.704	0.631	0.001*	0.903	0.138
P < 0.05 statistically significant *Statistically significant

Table 4

Variables associated with live birth analyzed by multivariate logistic regression.
	Standardized Coefficients
Variable	Beta	Standardized Error	Odds ratio (CI)	p-value
Age	-0.95	0.002	0.91 (0.86–0.98)	0.019*
Duration of Follicular Growth	0.74	0.007	0.51 (0.22–1.17)	0.72
Number of Dominant Follicile	-0.53	0.021	0.93 (0.81–1.07)	0.186
Endometrial Thickness	-0.01	0.59	0.99 (0.88–1.11)	0.86
Abbreviations: OR, Odds ratio; CI, Confidence interval P < 0.05 statistically significant *Statistically significant

This study aimed to assess the relationship between endometrial thickness (EMT) on the day of hCG injection and reproductive outcomes in patients undergoing ovulation induction with clomiphene citrate (CC) combined with intrauterine insemination (IUI). Our results demonstrate that an optimal EMT of 8–9 mm is associated with significantly higher clinical pregnancy and live birth rates, suggesting that EMT could be a useful biomarker for assessing uterine receptivity in CC + IUI cycles, despite its moderate predictive accuracy (sensitivity of 49.4% and specificity of 55.3%)(Fig. 1)(14, 15). The mean EMT in cases achieving clinical pregnancy was 8.38 mm, which aligns with previous research indicating better reproductive outcomes within this range(16, 17).

As various factors affect endometrial receptivity and thus treatment outcome, the prognostic value of EMT for achieving clinical pregnancy and live birth is controversial. Studies have shown mixed results; for instance, Kolibianakis et al. found no significant difference in EMT between women who achieved ongoing pregnancy and those who did not (7.6 ± 0.3 vs. 7.6 ± 0.2; P = 0.7)(18). Similarly, Masrour et al. and Liu et al. reported no predictive value of EMT for endometrial receptivity(19, 20). A systematic review and meta-analysis, which included 3846 women, also found no association between EMT and pregnancy rates, although the studies included were of low to moderate quality(21). Furthermore, more recent studies, such as Quass et al. and Mehrjerd et al., have reported no significant relationship between EMT and reproductive outcomes, although some findings suggested higher live birth rates with increasing EMT(22, 23).

Our study observed that pregnancy rates were higher at EMT values of 8–9 mm, potentially due to the anti-estrogenic effects of CC on the endometrium and cervical mucus, which are known to impact conception rates(24–26). This is consistent with the literature, where lower EMT values in CC cycles are often associated with higher pregnancy rates compared to COH-IUI or IVF-ET cycles(27, 28). Despite this, some studies have reported high pregnancy rates even with EMT as low as 5–6 mm(22).

Additionally, our study found a negative correlation between female age and pregnancy outcome, which is consistent with findings by Ghosh et al. and Esmailzadeh et al., who reported lower pregnancy rates in women over 30 (17, 29). The adverse effect of age on treatment outcomes is likely due to factors such as follicular depletion, decreased oocyte quality, and increased aneuploidy rates (30, 31).

Finally, our study highlighted that shorter infertility duration was associated with higher clinical pregnancy rates, which aligns with other studies reporting similar findings (32, 33). However, there is no consensus on the ideal duration of infertility for achieving favorable outcomes during treatment cycles.

4.1.Strenghts and limitations

To the best of our knowledges, this study is one of the largest retrospective study which is searching only CC-IUI from the assisted reproductive technique. In addition, one of the strongest aspects of this study is that it is one of the few studies that tried to find a threshold value for EMT on the day of the hCG trigger in infertile couples who underwent CC-IUI and also gave concretely viable pregnancy and spontaneous abortion rates according to the threshold value. Inclusion of only those with unexplained infertility and WHO category 2 normogonodotropic anovulatory patients in the study resulted in a more homogeneous patient group.

There are also many limitations of this study. One of these limitations is the retrospective design. Apart from this, although this study has a sufficient sample size to give an EMT threshold value, the low sensitivity and specificity of the threshold value obtained indicate that prospective studies with larger sample sizes are needed to give a threshold value with higher sensitivity and specificity. In addition, ultrasound measurements are inherently subjective even though the technique is standardized across the reproductive endocrinology clinics as mentioned in the method section. Among the possible limitations of the present study, we can mention that the endometrial pattern was not noted in the medical records of the patients, so it was not given by this study. Another limitation of this study was that endometrial thickness was not measured in 2–3 day cycles. Perhaps midcycle endometrial thickness is related to early follicular phase thickness.

In conclusion, our study found that an endometrial thickness (EMT) of 8–9 mm on the day of hCG trigger is associated with higher clinical pregnancy and live birth rates in CC + IUI cycles. However, due to the low sensitivity and specificity, and successful pregnancies occurring outside this range, setting a strict EMT threshold for cycle decisions is not advisable. Other factors such as female age and duration of infertility should also be considered. These findings can help optimize patient selection and treatment regimens, reducing unnecessary interventions and costs.

Ethical approval

This study was approved by Ministry of Health, Health Sciences University Etlik Zübeyde Hanım Women’s Institutional Board (30/12/2020-90057706-799) and all the patients consented to the use of their clinical data anonymously for scientific studies prior to the treatment cycles.

Consent for publication: Not applicable

Availability of data and material: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Conflict of interest: The author declare no conflicts of interest.

Funding: The study did not receive funding.

Authorship Contributions:

Conception and design of the study: AA, BD, SD Acquisition of data: AA, DS, AGE Analysis and/or interpretation of data: AA, BD, AGE Drafting the manuscript: AA, BD, SD

Acknowledgments: None.

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No competing interests reported.

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The Effect of Endometrial Thickness on The Day of Human Chorionic Gonadotropin Injection on Reproductive Outcome in Clomiphene Citrate and Intrauterine Insemination Cycles

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Abstract

Backround:

Methods

Results

Conclusion

Figures

1.Introduction

2.Methods

2.1.Study design

2.2.İnclusion-Exclusion criteria

2.3.Treatment Protocol

2.4.Statistical analysis:

3.Results

4.Discussion

4.1.Strenghts and limitations

5.Conclusion

Declarations

References

Additional Declarations

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