|Year : 2018 | Volume
| Issue : 1 | Page : 34-39
Tamoxifen is better than low-dose clomiphene or gonadotropins in women with thin endometrium (<7 mm) after clomiphene in intrauterine insemination cycles: A prospective study
Sunita Sharma, Geetha Rani, Gunja Bose, Indranil Saha, Sikha Bathwal, BN Chakravarty
ART Department, Institute of Reproductive Medicine, Kolkata, West Bengal, India
|Date of Web Publication||27-Mar-2018|
Dr. Sunita Sharma
HB-36/A/3, Salt Lake City, Sector-III, Kolkata - 700 106, West Bengal
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aim: Gonadotropin stimulation is used as the second line of treatment in patients with thin endometrium following clomiphene citrate (CC) administration, which is associated with higher cost, multiple births, and ovarian hyperstimulation syndrome. Tamoxifen (TMX), a selective estrogen receptor modulator, acts as an agonist on the endometrium. The objective of the present study was to compare the efficacy of low-dose CC, TMX, and gonadotropins in women with thin endometrium (<7 mm) following Clomiphene in intrauterine insemination (IUI) cycles. Settings and Design: A prospective observational study between December 2011 and June 2013 was carried out in a tertiary infertility center. Methods: Women (n = 502) undergoing IUI with endometrium <7 mm after 100 mg CC were included in the study and divided into three treatment groups. Women in Group A (n = 182, cycles = 364) received clomiphene (50 mg/day from day 3 to 7), Group B (n = 179, cycles = 342) received TMX (40 mg/day from day 3 to 7), and Group C (n = 141, cycles = 226) received continuous urine-derived follicle-stimulating hormone 75–150 IU from day 3 onward until human chorionic gonadotropin injection. Endometrial thickness (ET), pregnancy rate, and live birth rate were considered as main outcome measures. Statistical Analysis: Multiple comparisons using one-way ANOVA and Schiff's test were performed. Results: Pregnancy and live birth rate were significantly higher (P < 0.004) in TMX and gonadotropin groups compared to clomiphene. A number of follicles in the TMX group were found to be lower (P < 0.001) compared to other two groups. In polycystic ovary syndrome patients, ovulation induction with TMX resulted in inadequate response in more than half of the cycles. Conclusions: TMX can improve ET and live birth rate in patients with thin endometrium after clomiphene.
Keywords: Clomiphene, gonadotropin, intrauterine insemination, tamoxifen, thin endometrium
|How to cite this article:|
Sharma S, Rani G, Bose G, Saha I, Bathwal S, Chakravarty B N. Tamoxifen is better than low-dose clomiphene or gonadotropins in women with thin endometrium (<7 mm) after clomiphene in intrauterine insemination cycles: A prospective study. J Hum Reprod Sci 2018;11:34-9
|How to cite this URL:|
Sharma S, Rani G, Bose G, Saha I, Bathwal S, Chakravarty B N. Tamoxifen is better than low-dose clomiphene or gonadotropins in women with thin endometrium (<7 mm) after clomiphene in intrauterine insemination cycles: A prospective study. J Hum Reprod Sci [serial online] 2018 [cited 2020 Feb 18];11:34-9. Available from: http://www.jhrsonline.org/text.asp?2018/11/1/34/228614
| Introduction|| |
Isntrauterine insemination (IUI) is widely used as an empirical treatment for a large group of subfertile patients. It is inexpensive, easy to perform, and more acceptable to the couple when compared to in vitro fertilization (IVF)/intracytoplasmic sperm injection.
Clomiphene citrate (CC) continues to be the most commonly prescribed drug for ovarian stimulation in IUI cycles. Despite ovulation rate of 50%–75%, pregnancy rate per cycle is observed in only 10%–20% of cases , due to peripheral anti-estrogenic effect at the level of the endometrium with clomiphene. Furthermore, endometrial thinning has been observed in 15%–50% of CC users.,
To increase the endometrial thickness (ET), various strategies have been adopted to minimize the anti-estrogenic actions of CC but with limited success. Addition of systemic or vaginal estrogen along with CC treatment may increase ET., Low-dose aspirin supplements  and intravaginal sildenafil  modify uterine vascularity and improve ET. Other methods such as starting CC earlier in the cycle, use of aromatase inhibitors, and delaying the administration of human chorionic gonadotropin (hCG) have also been suggested. However, all these options to improve ET are controversial.
Treatment with gonadotropins and IUI has been shown to be highly successful in the treatment of patients having anti-estrogenic side effects with CC. Gonadotropin treatment raises several concerns, including the need for intensive monitoring, multiple pregnancy rate, which is equal to or higher than in IVF.
Tamoxifen (TMX) closely resembles CC both in structure and mode of action. It appears to have agonistic action on the endometrium. The increased estrogenic stimulation that has been observed with TMX action on the lower genital tract may be beneficial, especially for those suffering from an adverse response following the administration of CC. It was postulated that, by the administration of TMX, it might be possible to mimic the action of CC for the stimulation of ovarian follicles and avoid the adverse effects of CC on the endometrium.
The objective of the present study was to compare the efficacy of low-dose CC (50 mg), TMX, and gonadotropins in women with thin endometrium (<7 mm) following CC (100 mg) in IUI cycle.
| Methods|| |
This was a prospective observational study carried out at a private tertiary fertility center between December 2011 and June 2013. Approval was obtained from the Institutional Research Ethics Board (IRM/BNC-IHP 41/October 20, 2010). Written informed consent was taken from all the women included in this study.
The whole cohort included 502 women between 25 and 38 years undergoing 932 IUI cycles for the following indications: Male factor, anovulation, and unexplained infertility [Figure 1]. All patients included had thin ET after 100 mg of CC in an earlier cycle. Pelvic ultrasonography was performed, and patients with any uterine or adnexal pathology were excluded from the study. Patients who had taken tuberculosis treatment in the past were excluded from the study. All male partners with a total motile sperm count of <5 × 106/ml were excluded from the study. Infertile polycystic ovary syndrome (PCOS) women who had responded to CC previously, seeking IUI were included in the study.
|Figure 1: Number of patients, etiology, and performed intrauterine insemination cycle|
Click here to view
A hysterosalpingogram was performed to verify tubal patency and patients with at least one tube patent were included in the study. Endometriosis patients were excluded from the study. PCOS was defined according to the modified Rotterdam revised ESHRE/ASRM criteria. The diagnosis of unexplained infertility was based on normal findings in the seminal fluid analysis, mid-luteal serum progesterone, and hysterosalpingogram or laparoscopy.
A total of 502 women who had thin endometrium (<7 mm) after CC (100 mg) in IUI cycles were allocated into three groups in a serial order. Two months gap was given before ovulation induction in all three groups. Group A included 182 patients who had 364 stimulation cycles, received CC 50 mg/day from D3 to D7. Group B included 179 patients who had 342 stimulation cycles, received TM × 40 mg/day from D3 to D7. Group C included 141 patients who underwent 226 cycles, received urine-derived follicle-stimulating hormone (FSH) 75–150 IU starting from D3 till the day of hCG.
Transvaginal sonography for follicular monitoring was done from day 10 of menstruation onward. The internal diameter of each visible follicle was measured in two planes, and the average diameter was calculated. In addition, the ET was measured in the mid-sagittal plane from the outer to the outer edge of the endometrial-myometrial interfaces in the widest part of the endometrium. Ovulation was triggered with urinary hCG (5000 IU) when the leading follicle was ≥18 mm and ET ≥7 mm. In patients with ET <7 mm, ovulation trigger was postponed till the ET was ≥7 mm. Women with persistent ET <7 mm and/follicle >24 mm were also excluded from the study. The cycle was cancelled in 24 patients who had ≥4 follicles with ≥16 mm diameter.
The primary outcome measure was live birth rate and secondary outcome variables were ET, number of mature follicles, ovulation rate, cancellation rate, pregnancy rate, and miscarriage rate.
This study was approved by our Institute's Ethical Committee (IRM/BNC-IHP-41/20-10-2010).
Multiple comparisons using one-way ANOVA and Schiff's test were performed, wherever appropriate, between the three Groups A, B, and C. Data are expressed as mean ± standard deviation; statistical significance of the test was performed at the 5% level (P < 0.05).
| Results|| |
A total of 277 cycles were cancelled out of 932 cycles. The major cause of IUI cancellations in TMX group was an inadequate response or failure to achieve even one follicle ≥16 mm. On the contrary, over the response that led to the presence of too many mature follicles (>4 follicles ≥16 mm) was the main cause of cancellation in the gonadotropin group (43.63%). In low-dose CC group, thin endometrium and luteinized unruptured follicle were the major cause of cancellation. On-demand failure to obtain a semen sample was the other reason for cancellation [Figure 1]. In PCOS, women response to TMX was inadequate in 55.2% of cycles which were cancelled [Table 1]. The clinical profile including age, duration of infertility, body mass index, baseline FSH, and luteinizing hormone of patients belonging to Group A, B, and C undergoing IUI is comparable [Table 2]. Different cycle parameters of the three groups are shown in [Table 3]. The ovulation rate was found to be comparable in all groups. ET was found to be significantly higher in both TMX and gonadotropin group compared to low-dose CC group. A number of follicles in the TMX group were significantly less (P < 0.001) compared to CC or gonadotropin group. However, size of the follicle was significantly higher in group A compared to other two groups on the day of hCG. When we compared the clinical outcome, TMX and gonadotropin group showed similar pregnancy rate (14.52% vs. 14.89%) and live birth rate (12.2% vs. 12.7%). However, in low-dose CC group both pregnancy rate (P < 0.002) and live birth rate (P < 0.004) were statistically lower compared to TMX or gonadotropin groups [Table 4]. There were three cases of twin pregnancy in gonadotropin group [Table 4].
| Discussion|| |
Our study has evaluated the role of TMX in ovulation induction compared to gonadotropin and low-dose CC in women with thin endometrium following 100 mg CC. ET is a well-established parameter for prediction of pregnancy in assisted reproduction technique. Studies have shown that pregnancy and implantation rates for the patients with ET >7 mm were significantly higher than those of patients who showed a thinner endometrium., Furthermore, ET <8 mm on the day of hCG administration also increases the risk of biochemical pregnancy. Thin endometrium, the most common anti-estrogenic effect of CC for ovulation induction has been seen in 15%–50% of patients. This adverse effect of CC increases with higher doses. Hence, in our study, we have included group A, in which the patients were stimulated with a lower dose of CC (50 mg) so that the antiestrogenic effect on endometrium may be reduced. Gonadotropins were used as the next line of management in this subset of women. Gonadotropin therapy, although more effective than CC, not only burdens the patient with stress and medical expense but can also cause multiple pregnancy and ovarian hyperstimulation syndrome. Therefore, preventing CC induced thinning of the endometrium by alternative methods like TMX/aromatase inhibitors appears imperative. During our study period, letrozole (aromatase inhibitor) was banned for use in ovulation induction.
TMX, primarily developed for use in the treatment of breast cancer, is a selective estrogen receptor modulator that closely resembles CC in the mechanism of action. Published literature has reported ovulation rate of 50%–90% and pregnancy rate of 30%–50% following TMX. Like CC, TMX occupies estradiol-binding sites on the hypothalamic-pituitary axis and prevents the negative feedback effect of estradiol, resulting in increased endogenous gonadotropin secretion. Direct action on the ovary without involving hypothalamic-pituitary axis has also been suggested. TMX unlike CC acts as an agonist on the endometrium and cervical mucus. In the mid-luteal phase, TMX may enhance endometrial glycogen content thereby improving its receptivity. Moreover, its use for ovulation induction for short duration is not associated with increased risk of ovarian and endometrial cancer. Hence, it appears that TMX may be an alternative drug to gonadotropins in patients who had thin endometrium when treated with CC. Studies have observed that women having thin endometrium with CC (<7 mm) exhibited improved ET when TMX was used for ovulation induction in the subsequent cycle.,
A prospective study by Wang et al. compared TMX or CC along with alternate-day human menopausal gonadotropins for ovulation induction in patients with previously documented thin endometrium. They found that TMX group required longer duration and dose of gonadotropin stimulation with lesser number of mature follicles than CC group. They suggested that TMX may not be the first choice in patients with adequate endometrium, but they found a significantly increased ET and pregnancy rate in TMX group than CC. In line with the above findings, our study also observed improved ET following TMX. The pregnancy rate and live birth rate in TMX group were comparable to gonadotropin group but significantly better than CC group. However, in PCOS women, we observed higher cycle cancellation rate following TMX due to inadequate response. This subset of women had shown a good follicular response to CC (100 mg) in the previous cycle. Therefore, it appears that TMX is not as efficacious as CC for ovulation induction in PCOS women. Similar to our observation, a randomized controlled trial conducted by Badawy et al. showed a significantly lower ovulation rate following TMX compared to CC in PCOS women. They concluded CC had more ovulatory cycle than TMX in PCOS women.
This is in contrast to the meta-analysis which concluded that there are no appreciable differences in ovulation or pregnancy rates after treatment with TMX or CC in anovulatory infertility. Dhaliwal et al. reported TMX to be a good alternative to CC for ovulation induction in CC-resistant and CC failure PCOS patients. They had started with TMX 40 mg/day and increased it to 80 mg/day in nonresponders. A recent Cochrane review comparing the efficacy of anti-estrogens in PCOS women also reported similar pregnancy and live birth rates with CC and TMX.
In our study, we have noted that the size of leading follicle in CC group on the day of hCG trigger was greater (P < 0.001) compared to the gonadotropin and TMX group. This is because many patients in the CC group had ET <7 mm when the follicular size reached ≥18 mm, and hence, hCG administration was delayed till ET reached ≥7 mm, which resulted in greater follicular diameter. We also observed higher luteinized unruptured follicles in CC group. The number of cancellations due to over response following gonadotropins was higher probably due to increase in dose of gonadotropin on day 7, when inadequate response was noted. Although the mechanism of action is similar in both TMX and CC, we observed a significantly lesser number of follicles following induction with TMX.
| Conclusions|| |
TMX (40 mg) appears to be a promising drug in women with thin endometrium following CC (100 mg). It seems to be less effective in women with PCOS who responded well with CC (100 mg). Further larger well-designed trials are warranted to support the findings.
We are sincerely thankful to Mr. Asish Shit for technical assistance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
ESHRE Capri Workshop Group. Intrauterine insemination. Hum Reprod Update 2009;15:265-77.
Garcia J, Jones GS, Wentz AC. The use of clomiphene citrate. Fertil Steril 1977;28:707-17.
Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update 1996;2:483-506.
Nakamura Y, Ono M, Yoshida Y, Sugino N, Ueda K, Kato H, et al.
Effects of clomiphene citrate on the endometrial thickness and echogenic pattern of the endometrium. Fertil Steril 1997;67:256-60.
Homburg R. Clomiphene citrate – End of an era? A mini-review. Hum Reprod 2005;20:2043-51.
Gerli S, Gholami H, Manna C, Di Frega AS, Vitiello C, Unfer V, et al.
Use of ethinyl estradiol to reverse the antiestrogenic effects of clomiphene citrate in patients undergoing intrauterine insemination: A comparative, randomized study. Fertil Steril 2000;73:85-9.
Cetinkaya K, Kadanalı S. The effect of administering vaginal estrogen to clomiphene citrate stimulated cycles on endometrial thickness and pregnancy rates in unexplained infertility. J Turk Ger Gynecol Assoc 2012;13:157-61.
Check JH, Dietterich C, Lurie D, Nazari A, Chuong J. A matched study to determine whether low-dose aspirin without heparin improves pregnancy rates following frozen embryo transfer and/or affects endometrial sonographic parameters. J Assist Reprod Genet 1998;15:579-82.
Sher G, Fisch JD. Vaginal sildenafil (Viagra): A preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF. Hum Reprod 2000;15:806-9.
Wu CH, Winkel CA. The effect of therapy initiation day on clomiphene citrate therapy. Fertil Steril 1989;52:564-8.
Badawy A, Mosbah A, Shady M. Anastrozole or letrozole for ovulation induction in clomiphene-resistant women with polycystic ovarian syndrome: A prospective randomized trial. Fertil Steril 2008;89:1209-12.
Dickey RP, Olar TT, Taylor SN, Curole DN, Matulich EM. Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: Effect of clomiphene citrate alone and with human menopausal gonadotropin. Fertil Steril 1993;59:756-60.
Eijkemans MJ, Polinder S, Mulders AG, Laven JS, Habbema JD, Fauser BC, et al.
Individualized cost-effective conventional ovulation induction treatment in normogonadotrophic anovulatory infertility (WHO group 2). Hum Reprod 2005;20:2830-7.
Deligdisch L. Hormonal pathology of the endometrium. Mod Pathol 2000;13:285-94.
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41-7.
Kovacs P, Matyas S, Boda K, Kaali SG. The effect of endometrial thickness on IVF/ICSI outcome. Hum Reprod 2003;18:2337-41.
Coulam CB, Bustillo M, Soenksen DM, Britten S. Ultrasonographic predictors of implantation after assisted reproduction. Fertil Steril 1994;62:1004-10.
Takasaki A, Tamura H, Taketani T, Shimamura K, Morioka H, Sugino N, et al.
A pilot study to prevent a thin endometrium in patients undergoing clomiphene citrate treatment. J Ovarian Res 2013;6:94.
Borenstein R, Shoham Z, Yemini M, Barash A, Fienstein M, Rozenman D, et al.
Tamoxifen treatment in women with failure of clomiphene citrate therapy. Aust N
Z J Obstet Gynaecol 1989;29:173-5.
Tajima C, Fukushima T. Endocrine profiles in tamoxifen-induced ovulatory cycles. Fertil Steril 1983;40:23-30.
Fukushima T, Tajima C, Fukuma K, Maeyama M. Tamoxifen in the treatment of infertility associated with luteal phase deficiency. Fertil Steril 1982;37:755-61.
Cook LS, Weiss NS, Schwartz SM, White E, McKnight B, Moore DE, et al.
Population-based study of tamoxifen therapy and subsequent ovarian, endometrial, and breast cancers. J Natl Cancer Inst 1995;87:1359-64.
Reynolds K, Khoury J, Sosnowski J, Thie J, Hofmann G. Comparison of the effect of tamoxifen on endometrial thickness in women with thin endometrium (<7mm) undergoing ovulation induction with clomiphene citrate. Fertil Steril 2010;93:2091-3.
Wang CW, Horng SG, Chen CK, Wang HS, Huang HY, Lee CL, et al.
Ovulation induction with tamoxifen and alternate-day gonadotrophin in patients with thin endometrium. Reprod Biomed Online 2008;17:20-6.
Badawy A, Gibreal A. Clomiphene citrate versus tamoxifen for ovulation induction in women with PCOS: A prospective randomized trial. Eur J Obstet Gynecol Reprod Biol 2011;159:151-4.
Steiner AZ, Terplan M, Paulson RJ. Comparison of tamoxifen and clomiphene citrate for ovulation induction: A meta-analysis. Hum Reprod 2005;20:1511-5.
Dhaliwal LK, Suri V, Gupta KR, Sahdev S. Tamoxifen: An alternative to clomiphene in women with polycystic ovary syndrome. J Hum Reprod Sci 2011;4:76-9.
] [Full text]
Brown J, Farquhar C. Clomiphene and other antioestrogens for ovulation induction in polycystic ovarian syndrome. Cochrane Database Syst Rev 2016;12:CD002249.
[Table 1], [Table 2], [Table 3], [Table 4]