A randomized controlled trial comparing combination of letrozole and clomiphene citrate or letrozole alone for ovarian stimulation in infertile women.

In both Groups (1 and 2), most of the women were aged between 31 and 35 years (46.7% and 61.1%, respectively). Statistically, age was comparable between the treatment groups. 74.4% and 77.8% women were housewives from group 1 and group 2, respectively. No significant difference was found between the groups in terms of occupation. 66.7% and 68.9% women belonged to BMI category 18–22.9 kg/m 2 in group 1 and group 2, respectively. Statistically, the two groups were comparable in terms of the BMI of the patients included in the study [ Table 1 ]. Demographic distribution of study population Majority of the women in both the groups had Primary Infertility (Group 1: 91.1%; Group 2: 95.6%). There was no significant difference was found between the treatment groups for Infertility type. Duration of infertility was slightly longer in Group 1 as compared to Group 2; however, this difference was not significant. For majority of the women in Group 1 and 2, Majority of women had unexplained cause of infertility (73.3% and 77.8%, respectively) [ Table 2 ]. Intergroup comparison of type of infertility, duration, and causes At Day two, endometrial thickness was 5.31 ± 1.11 in Group 1 and 5.38 ± 0.78 in Group 2. On statistical analysis, ET was comparable at Day two between the groups. The Antral-follicular count was 5.33 ± 1.71 in Group 1 and 5.10 ± 2.37 in Group 2, however statistically this difference was not-significant [ Table 3 ]. Intergroup comparison of endometrial thickness at and antral follicular count at day 2 At the Day of trigger, endometrial thickness was 7.58 ± 1.30 in Group 1 and 7.22 ± 0.90 in Group 2. The developing follicular count was 2.57 ± 0.92 in Group 1 and 2.04 ± 0.83 in Group 2, statistically, Group 2 had significantly lower follicular count [ Table 4 ]. Intergroup comparison of endometrial thickness and follicular count at day of trigger Number of follicular ruptures was significantly higher in group 1. More than three follicles ruptured in 11.1% women in group 1 compared to group 2 (2.2%). 40% women in group 1 had three ruptured follicles compared to 21.1% in group 2. 46.7% women in group 1 had at least one ruptured follicle compared to 73.3% women in group 2. None of the follicle got ruptured in 2.2% women in group 1 and 3.3% women in group 2 [ Table 5 ]. Intergroup comparison of number of follicular ruptures χ 2=16.121; P =0.001 The conception rate was 4.4% in group 1 as compared to 3.3 percent in group 2. this difference was not statistically significant [ Table 6 ]. On the comparing Side effects between the groups statistically, no significant difference was found between both the groups [ Table 7 ]. Intergroup comparison of IUI and conception in present cycle Intergroup comparison of side-effects χ 2 =1.921; P =0.589

Infertility is defined by failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse. This condition may be further classified as primary infertility, in which no previous pregnancies have occurred, and secondary infertility, in which a prior pregnancy, although not necessarily a live birth, has occurred.[ 1 ] According to data from District Level Household and Facility Survey carried out in India during 2007 to 2008, 8.8% of married women reported infertility, of whom 6.75% had primary infertility and 2.1% has secondary infertility. Various studies from different regions of India have reported the prevalence of primary infertility varying from 8.9% to 14.2%.[ 2 ] Infertility may be caused by several different factors, in either the male or female reproductive systems. In the female reproductive system, infertility may be caused by: tubal disorders such as blocked fallopian tubes, which are in turn caused by untreated sexually transmitted infections (STIs) or complications of unsafe abortion, postpartum sepsis or abdominal/pelvic surgery; uterine disorders that could be inflammatory in nature (such as such endometriosis), congenital in nature (such as septate uterus), or benign in nature (such as fibroids); disorders of the ovaries, such as polycystic ovarian syndrome and other follicular disorders. Disorders of the endocrine system causing imbalances of reproductive hormones.[ 3 ] Thirty percent of couples are diagnosed with unexplained infertility, in which the basics infertility evaluation reveals normal semen parameters, evidence of ovulation, patent fallopian tubes, and no other obvious cause of infertility. Historically, unexplained infertility was often treated with superovulation using clomiphene, letrozole, or gonadotropins in a stepwise approach, combined with intrauterine insemination (IUI) (e.g. CC/IUI/, letrozole/IUI, and FSH/IUI) followed by ART. Despite research findings supporting the use of IVF as first–line treatment for unexplained infertility, superovulation/IUI treatments have continued to be widely used, presumably because they are less expensive than IVF on per–cycle basis and in some countries like India, ovulation induction/IUI may be much more accessible than IVF.[ 4 ] Clomiphene citrate (CC) is a commonly prescribed pharmacologic agent used to induce ovulation in women with PCOS. Letrozole may offer a benefit over CC for ovulation induction because it does not block estrogen receptors in both central and peripheral target tissues, and normal central feedback mechanisms remain intact. Because letrozole and clomiphene have different mechanisms of action, we postulated that combination of this medication may result in an improved ovulatory rate over letrozole alone. Combination of letrozole and clomiphene have been studied in past but there are fewer studies in Indian scenario. So, we decided to study the role of clomiphene and letrozole together in the increasing the efficacy of ovulation induction: keeping in mind the cost factor of gonadotropins.

Hence, it was concluded that both the regimes i.e. combination of CC plus Letrozole and Letrozole-alone were equally efficacious and safe to use in the treatment of female infertility with Letrozole-alone regime being slightly more effective in terms of endometrial thickness at trigger. Informed consent was taken from all the participants. Approved by Institutional Ethics Committee of King Georges Medical University. (Reference number- Ref. no. XIV-PGTSC-IIA/P82. CTRI registration done with Number CTRI/2023/03/050914. There are no conflicts of interest.

The present study was conducted to compare combination of Letrozole and CC with Letrozole alone for ovarian stimulation in infertile women among 180 women randomized equally into two groups. Group 1 received combination of Letrozole and CC, while Group 2 received Letrozole alone. In the present study no significant difference was observed for age between the two groups with mean age of 32 years for both the groups. Maximum women in both the groups were between 31–35 years of age, Majority of the women in both the groups were housewives. Chera-Aree et al .[ 5 ] found comparable mean age of 31.8 years in combination group and 32.4 years in Letrozole alone group. Mejia et al .[ 6 ] reported average age range of 30–31 years in the study population like the present study. However, they reported a comparatively higher body mass index, among the study participants (33–34 kg/m 2 ). Age plays a crucial role in infertility. Body mass index (BMI) can significantly impact female fertility. Women with a BMI outside the normal range (18.5 to 24.9) are at increased risk of ovulation disorders. Excess body weight, especially in the form of abdominal fat, can lead to insulin resistance and hormonal imbalances, disrupting ovulation. It was observed in present study that duration of infertility between the two groups was comparable, with maximum patients in group 1 (46.7%) and group 2 (48.9%) were for 2–3 years. Chera-Aree et al .[ 5 ] reported concurrent findings of median duration of attempts to conceive in combination group and Letrozole alone group (2 years in both the groups). Mejia et al .[ 6 ] reported concurrent findings to our study. Delaying seeking fertility evaluation and treatment can result in missed opportunities for timely intervention and may prolong the time it takes to achieve a successful pregnancy. The duration of infertility may influence the type and timing of fertility treatments pursued by couples.[ 7 ] Majority of the women in both the groups had Primary Infertility (Group 1: 91.1%; Group 2: 95.6%), Type and causes of infertility were comparable between the treatment groups. Magdum et al .[ 8 ] in a cross sectional study, among 111 women present with complaints of not conceiving naturally. Amongst them primary infertility was found among 81% and secondary infertility among 19% women. Endometrial thickness can indeed play a role in infertility, as it is crucial for embryo implantation and successful pregnancy. Inadequate endometrial thickness or quality can lead to implantation failure, where the embryo fails to implant or is unable to establish a successful pregnancy.[ 9 10 ] Endometrial thickness on day 2 of the menstrual cycle was not significantly different between group 1 (5.31 mm) and group 2 (5.38 mm). On day of trigger significant difference was observed in endometrial thickness between group 1 and group 2 (7.22 mm and 7.58 mm, respectively). In group 2 endometrial thickness significantly better than group 1, receiving CC and Letrozole together as CC is known to cause endometrial thinning. Chera-Aree et al. ,[ 5 ] while comparing combination of CC and letrozole with CC alone observed no significant difference in endometrial lining thickness between the groups (combination group: 6.85 mm and Letrozole alone group: 7.40 mm). Mejia et al .[ 6 ] reported significantly thicker endometrium for women in combination group (8.3 mm) compared to Letrozole alone group (6.2 mm). In present study there was no significant difference in antral-follicular count at day two with 5.33 in group 1 and 5.10 in group 2. Follicular Count at Day of Trigger was significantly higher in group 1 (2.57) as compared to group 2 (2.04). Number of follicular ruptures was significantly higher in group 1. Less than half (46.7%) women in group 1 had 1–2 ruptured follicle compared to 73.3% women in group 2. 40% women in group 1 had 3 ruptured follicles compared to 21.1% in group 2. More than three follicles ruptured in 11.1% women in group 1 compared to group 2 (2.2%). None of the follicle got ruptured in 2.2% women in group 1 and 3.3% women in group 2. Mejia et al .[ 6 ] also reported significantly higher proportion of women with >10 mm in combination group (one patient) compared to Letrozole alone group (no patient). There is no significant difference between group 1 and group 2 with respect to IUIs. IUI performed in 97.8% in Group 1 and 100% in Group 2. While Conception was achieved in four women in Group 1 and 3 women in Group 2. Bahadur et al .[ 11 ] observed higher conception rate in combination group (9.3%) compared to Letrozole-alone group (6.3%) in first induction cycle. (statistically not significant). In present study there was no significant association for number of ruptured follicles and conception of pregnancy. Overall, seven patients conceived, among them four patients conceived where 1–2 ruptured follicles, two patients conceived where >3 follicle ruptured and one patient conceived where three follicles ruptured. Nambiar[ 12 ] found that the pregnancy rate was 35.1%, when follicular rupture happened at a mean diameter of 25 mm or less, and 34% when it occurred at a mean diameter more than 25 mm. There was no statistically significant difference observed in conception rate amongst both groups. Limited sample size in our study may reduce the study’s ability to draw definitive conclusions or detect subtle differences in outcomes and longer follow-up periods may be necessary to assess the cumulative impact of the treatment on fertility outcomes.

Open label prospective randomized control study. The study was conducted in the Department of Obstetrics and Gynaecology of King George’s Medical University, Lucknow. One year (March 2023 to February 2024). The sample size was calculated based on a previous article; 95% level of confidence and Error rate, usually set at 0.05 level is four. n = Z 2 P (1 − P )/d 2 where, n = sample size, Z = Z statistic for a level of confidence, for the level of confidence of 95%, which was conventional, Z value is 1.96. P = expected prevalence or proportion (in proportion of one; if 10%, P = 0.1), d = precision (in proportion of one; if 5%, d = 0.05). Ethical clearance was taken from Institutional Ethical Committee). Clinical Trial registration done. Total 180 women (90 women as cases and 90 as controls) included in this study. Informed consent was taken from all the participants. All Patients were evaluated based on history, general physical examination, clinical examinations, and relevant investigations. Women given written informed consent was taken. Healthy female subjects with unexplained infertility. Age: 18 to 40 years (inclusive) at the first screening visit in QMH (Department of Obstetrics and Gynaecology, KGMU, Lucknow). Women given written informed consent was taken. Healthy female subjects with unexplained infertility. Age: 18 to 40 years (inclusive) at the first screening visit in QMH (Department of Obstetrics and Gynaecology, KGMU, Lucknow). Not giving consent current hormonal contraception use bilateral tubal blockade Uncorrected thyroid disease Untreated hyperprolactinemia Medical conditions (i.e., uncontrolled type 1 or 2 diabetes mellitus, hypertension). Not giving consent current hormonal contraception use bilateral tubal blockade Uncorrected thyroid disease Untreated hyperprolactinemia Medical conditions (i.e., uncontrolled type 1 or 2 diabetes mellitus, hypertension). Diagnosis of infertility, defined as the inability of couple to achieve a pregnancy after 12 months of regular timed unprotected intercourse in women <35 years of age or after 6 months in women ≥35 years of age. For this study, various tools were employed including transvaginal sonography (TVS) for the clinical assessment of pregnancy, along with standard medical equipment for administering IUI and medications. SNOSE, The Sequentially Numbered Opaque Sealed Envelopes. A data collection sheet was utilized to collect data from all the cases and control. The primary technique involved in the study was the administration of pharmaceutical intervention with either letrozole and CC or letrozole alone based on random number table. Transvaginal ultrasound was being done from day two of menstrual cycle, with interval until follicular rupture and IUI were done. All participating women provided written informed consent before their inclusion in the study. They were then asked questions to gather essential information such as age, parity, occupation, income, and the underlying cause of infertility. Participants were randomized to either the case group, where they received Tab CC 50 mg OD and Tab Letrozole 5 mg OD from day 2/3 to day 6/7, or to a comparison group that received Tab Letrozole 5 mg OD from day 2/3 today 6/7. Follow-up performed on alternate day after day seven until follicle size reaches 18–20 mm, trigger given as inj Hcg 10,000 IU. Patient were asked to come after 36 hours with partner for IUI, else timed intercourse advised. All statistical analyses were performed using the SPSS (Statistical Package for Social Sciences) version 21.0 Statistical Analysis Software. The results were presented using various statistical methods to ensure the clarity and precision in the findings. Frequencies, percentages, and mean values along with standard deviations (mean ± SD) were meticulously calculated to provide a comprehensive overview of the data collected. For comparing categorical variables, the Chi-square test had been employed, while the Unpaired t -test was utilized for the analysis of continuous variables. A P value of less than 0.05 was established as the threshold for statistical significance, ensuring that the findings were robust and reliable.