Clomiphene citrate affects the receptivity of the uterine endometrium

Nakagawa, Koji; Kaneyama, Masayo; Nishi, Yayoi; Sugiyama, Rie; Motoyama, Hiroshi; Sugiyama, Rikikazu

doi:10.1007/s12522-014-0195-z

Cited by 12 publications

(11 citation statements)

References 26 publications

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“…The negative impact of clomiphene citrate on endometrial receptivity was recently suggested by Nakagawa et al, 25 who reported lowered pregnancy rates in frozen-thawed IVF cycles up to 90 days after stimulation by clomiphene citrate.…”

Section: Discussionmentioning

confidence: 78%

Effect of clomiphene citrate on uterine hemodynamics in women with unexplained infertility

Omran

El-Sharkawy

El-Mazny

et al. 2018

IJWH

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PurposeThe aim of the study was to evaluate the effect of clomiphene citrate on uterine artery blood flow using pulsed Doppler and endometrial and subendometrial micro vascularization using 3D power Doppler in unexplained infertility.Patients and methodsIn a prospective observational study at a university teaching hospital, the mid-luteal (peri-implantation) endometrial thickness and volume, uterine artery pulsatility index (PI) and resistance index (RI), endometrial and subendometrial vascularization index (VI), flow index (FI), and vascularization flow index (VFI), and serum estradiol and progesterone levels were compared between natural and clomiphene citrate stimulated cycles in the same group of 50 patients with unexplained infertility. Statistical analysis was done using paired t-test to compare different study variables.ResultsThe primary outcome, which was the endometrial flow index, was significantly lower in the stimulated cycles (mean ± SD: 23.89±7.96 vs 27.49±8.73, mean difference (95% CI): −3.6 (−2, −5.9); P=0.03). The mean ± SD of endometrial thickness (10.92±3.04 vs 12.46±3.08 mm; P=0.01), volume (4.57±1.28 vs 5.26±1.32 cm3; P=0.009), endometrial VI (0.86±0.15 vs 0.95%±0.21%; P=0.02), VFI (0.25±0.08 vs 0.31±0.12; P=0.004), subendometrial VI (1.93±0.68 vs 2.26%±0.75%; P=0.02), FI (26.81±9.16 vs 30.73±9.87; P=0.04), and VFI (0.68±0.18 vs 0.79±0.21; P=0.006) were significantly lower in the stimulated cycles. However, there were no significant differences in the uterine artery PI (P=0.12) and RI (P=0.08) or serum estradiol (P=0.54) and progesterone (P=0.37) levels between natural and stimulated cycles.ConclusionPeri-implantation endometrial perfusion is significantly lower in clomiphene citrate stimulated cycles when compared to natural ones in patients with unexplained infertility.

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Section: Discussionmentioning

confidence: 78%

Effect of clomiphene citrate on uterine hemodynamics in women with unexplained infertility

Omran

El-Sharkawy

El-Mazny

et al. 2018

IJWH

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“…In addition, clomiphene citrate is a highly potent prostaglandin synthesis inhibitor being comparable in this regard to indomethacin, thus raising concentrations of prostaglandin dehydrogenase in the endometrium [24] ; which negatively affects the implantation process. This was evident in the study of Nakagawa et al [25] who found that pregnancy rates following fresh embryo transfer for ovarian stimulation cycles using clomiphene citrate were poor (24.0%) even if hormonal treatment was given after clomiphene citrate treatment and endometrial thickness was recovered.…”

Section: Discussionmentioning

confidence: 95%

Sildenafil citrate adjuvant treatment in women with polycystic ovary syndrome following clomiphene failure: A randomized controlled trial

Ashoush

Abdelshafy

2019

Evidence Based Women's Health Journal

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Objective: The widespread classic PCOS treatment algorithm, consisting of 6-12 cycles of clomiphene followed by shifting to gonadotropins in case of failure to conceive, doesn't really address the cause of failure to conceive despite documented ovulation. Sildenafil citrate improves uterine blood flow, enhances endometrial development and modulates endometrial receptivity. Hence, this study monitored the ovarian response, endometrial development and subendometrial Doppler changes in PCOS women with previous clomiphene citrate failure following the use of adjuvant sildenafil citrate instead of shifting to gonadotropins. Patients and Methods: A double-blinded randomized controlled trial was conducted in Ain-Shams University Women's Hospital on 850 PCOS women with clomiphene failure. Those were randomized to clomiphene therapy, either with adjuvant placebo or sildenafil citrate (25 mg orally 6 hourly), starting from the 6th day till the end of the cycle. Folliculometry, every other day, started on the 10th day of the cycle. When ≥1 follicle reached a size ≥18mm, transvaginal ultrasound assessment of the endometrium and uterine/subendometrial Doppler was done. The resulting pregnancy rates were recorded. Results: The sildenafil group developed higher endometrial thickness (10.6±1.3 versus 9.4±1.5; p<0.001), a higher percentage of women with trilaminar endometrium (78.35% versus 59.76%; p<0.001) was found while the lower percentage was found with subendometrial and uterine artery Doppler indices (p<0.001 for all). It also developed higher pregnancy rates (43.7% versus 34.5%, p=0.006; NNT=10.8, 95% CI: 6.36-37.84). Conclusion: Sildenafil adjuvant therapy significantly increased pregnancy rates, improved endometrial development in terms of endometrial thickness and pattern as well as uterine and subendometrial blood flow.

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“…In contrast, no adverse effect of CC administration on pregnancy outcomes was observed after SVBT. A previous study reported that a cleaved ET, which included single and double embryo transfer, within 90 days after the last CC treatment resulted in a lower pregnancy rate compared with that for transfers at more than 90 days after CC treatment (Nakagawa et al , 2015). However, in their study, FSH and HCG were also used for ovarian stimulation.…”

Section: Discussionmentioning

confidence: 99%

“…Uncertainty remains regarding the duration of the effect of CC on uterine receptivity in the endometrium. Nakagawa et al (2015) previously demonstrated the long-term adverse effects of minimal ovarian stimulation with CC on pregnancy outcomes after either single or multiple ETs in a hormone replacement cycle; however, FSH and HCG were also used for ovarian stimulation, which may have affected their results. Moreover, their study included single and multiple ETs; thus, an evaluation of the actual effect of CC administration on uterine receptivity is challenging.…”

Section: Introductionmentioning

confidence: 99%

Comparison of pregnancy outcomes following fresh and electively frozen single blastocyst transfer in natural cycle and clomiphene-stimulated IVF cycles

Kato¹,

Ezoe²,

Yabuuchi³

et al. 2018

Human Reproduction Open

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STUDY QUESTION Are there any differences in live birth rates (LBR) following fresh blastocyst transfer in natural or clomiphene-stimulated cycles, or after elective blastocyst freezing in clomiphene-stimulated cycles followed by thawing and transfer at different time-points? SUMMARY ANSWER Clomiphene citrate (CC) administration adversely affected the LBR after single fresh blastocyst transfer (SBT) in CC cycles compared with that in natural cycles, while this adverse effect of CC is not present when a single vitrified-warmed blastocyst transfer (SVBT) is performed in subsequent natural ovulatory cycles, regardless of the duration between CC administration and the day of SVBT. WHAT IS KNOWN ALREADY CC affects uterine receptivity associated with a thinning of the uterine endometrium through an antioestrogenic effect. However, the duration that this adverse effect of CC on uterine endometrium persists after initial use is still unknown. STUDY DESIGN, SIZE, DURATION A retrospective cohort study of 157 natural cycle IVFs followed by SBT and 1496 minimal ovarian stimulation with CC IVF cycles followed by SBT ( n = 24) or SVBT ( n = 1472) from January 2010 to December 2014 was conducted. SVBT cycles were classified into two groups according to the period between the last day of CC administration and the day of SVBT (A: ≤60 d and B: ≥61 d). All groups were then compared based on pregnancy outcomes (natural-SBT group: n = 157, CC-SBT group: n = 24, SVBT-A: n = 1143, SVBT-B: n = 329). PARTICIPANTS/MATERIALS, SETTING, METHODS Women were aged 30–39 years at oocyte retrieval. In SVBT cycles, blastocysts were vitrified and warmed using a Cryotop safety kit. SVBT was performed in subsequent natural ovulatory cycles. The main outcomes were LBR and neonatal outcome, and both were compared among the groups. MAIN RESULTS AND THE ROLE OF CHANCE The LBR in the CC-SBT group (29.2%, 7/24) was significantly lower compared with the natural-SBT (56.1%, 88/157) ( P = 0.01) and SVBT-A (50.0%, 572/1143) ( P = 0.04), but not SVBT-B (47.4%, 156/329), groups. Furthermore, multivariate logistic regression analysis revealed that the LBR was comparable among the natural-SBT and SVBT groups, but was significantly lower in the CC-SBT group (adjusted odds ratio: 0.324, 95% CI: 0.119–0.800, P = 0.01). No significant differences among all groups were observed for gestational age ( P = 0.19), birthweight ( P = 0.41) and incidence of malformation ( P = 0.53). LIMITATIONS, REASONS FOR CAUTION In this study we analysed a biased sampl...

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Clomiphene citrate affects the receptivity of the uterine endometrium

Abstract: A lower PR was shown by the patients who underwent thawed ET in the HRC within 90 days after their last CC treatment, which shows that CC affects the receptivity of the uterine endometrium.

Cited by 12 publications

References 26 publications

Effect of clomiphene citrate on uterine hemodynamics in women with unexplained infertility

Effect of clomiphene citrate on uterine hemodynamics in women with unexplained infertility

Sildenafil citrate adjuvant treatment in women with polycystic ovary syndrome following clomiphene failure: A randomized controlled trial

Comparison of pregnancy outcomes following fresh and electively frozen single blastocyst transfer in natural cycle and clomiphene-stimulated IVF cycles

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