|Year : 2018 | Volume
| Issue : 2 | Page : 74-80
Comparison of ovarian reserve and response to gonadotropin stimulation in fertile and infertile Indian women based on ovarian reserve markers, anti-Mullerian hormone and antral follicle count
Jasneet Kaur, Nalini Mahajan
Department of Reproductive Medicine, Mother and Child Hospital, New Delhi, India
|Date of Web Publication||22-Feb-2019|
Department of Reproductive Medicine, Mother and Child Hospital, D-59 Defence Colony, New Delhi - 110 024
Source of Support: None, Conflict of Interest: None
Background: Poor ovarian response to gonadotropin (GT) stimulation during assisted reproductive technology cycles is often encountered in infertile women and is considered to be a cause of their infertility. Poor ovarian response is mostly a result of a low ovarian reserve (OR), implying that there may be an earlier depletion of the oocyte pool in infertile women.
Aim of the Study: To evaluate whether infertile Indian women below the age of 35 years have an earlier depletion of their OR and a lower ovarian response to GT in comparison to age-matched fertile controls.
Materials and Methodology: A total of 146 women undergoing in vitro fertilization-intracytoplasmic sperm injection at our fertility center between March 2017 and August 2017 were prospectively enrolled in this study. Anti-Mullerian hormone and antral follicle count (AMH and AFC) assessment was done for women enrolled in the study in the early follicular phase. Flexible GnRH antagonist protocol was followed. Age, AMH, AFC, body mass index, and response to ovarian stimulation (OS) were compared between the fertile and infertile groups. We also sought to determine which among these had the best prediction for ovarian response to controlled OS.
Statistical Analysis: Chi-square test was used for comparisons between study groups with respect to percentages. P < 0.05 was considered to be statistically significant.
Results: When adjusted for the differences in the demographic variables, we found no difference in the AMH (P = 0.298) and AFC (P = 0.302) between the fertile and infertile women. In addition, there was no difference in the ovarian response; the mean number of oocytes retrieved was 15.8 ± 7.5 in the fertile group and 14.3 ± 7.5 in the infertile group (P = 0.510). AMH had the strongest correlation with the number of oocytes retrieved (r = 2.11) in comparison to AFC (r = 0.08) and age (r = −0.45)
Conclusion: There is no difference in OR and response in fertile and infertile Indian having similar demographics and basal characteristics.
Keywords: Anti-Mullerian hormone, antral follicle count, Indian ethnicity, ovarian reserve, ovarian response
|How to cite this article:|
Kaur J, Mahajan N. Comparison of ovarian reserve and response to gonadotropin stimulation in fertile and infertile Indian women based on ovarian reserve markers, anti-Mullerian hormone and antral follicle count. Onco Fertil J 2018;1:74-80
|How to cite this URL:|
Kaur J, Mahajan N. Comparison of ovarian reserve and response to gonadotropin stimulation in fertile and infertile Indian women based on ovarian reserve markers, anti-Mullerian hormone and antral follicle count. Onco Fertil J [serial online] 2018 [cited 2019 Jul 18];1:74-80. Available from: http://www.tofjonline.org/text.asp?2018/1/2/74/252694
| Introduction|| |
Poor ovarian response to gonadotropin (GT) stimulation during assisted reproductive technology (ART) cycles is often encountered in infertile women and is considered to be a cause of their infertility. Poor ovarian response is mostly a result of a low ovarian reserve (OR), implying that there may be an earlier depletion of the oocyte pool in infertile women. Race and ethnicity may lead to variations in OR and this could be reflected in a poorer ART outcome. Studies comparing pregnancy and live birth rates among various ethnic groups have shown lower results in women of Asian ethnicity compared to their Caucasian counterparts.,,,,, Environmental, nutritional, and lifestyle-related factors have been implicated as causative agents. Latent genital tuberculosis (GTB) which is widespread in India is also thought to be a contributory factor. It is reported to cause an accelerated decline in OR and a poor ovarian response to GTs.
Evaluation of OR is essential to predict response to ovarian stimulation (OS), the success of in vitro fertilization (IVF) being associated with the number of oocytes retrieved., OR, constituted by the size of the ovarian follicle pool and quality of oocytes, declines with increasing age, principally due to apoptotic loss of primordial follicles. Currently, Anti-Mullerian hormone and antral follicle count (AMH and AFC) are considered the best biomarkers for OR and ovarian response, with age being the only marker that is predictive of oocyte quality. Prediction of ovarian response to GT stimulation by integrating various traditional hormonal, functional, and genetic biomarkers is often unreliable.
A cutoff age limit for depletion in OR and Pregnancy rates (PR) has been taken as 35 for the Caucasian population and this cutoff age has been used globally for all ethnic groups. Since poorer ART results have been reported for young women of Indian ethnicity, the present study was planned to evaluate whether infertile Indian women below the age of 35 years have an earlier depletion of their OR and a lower ovarian response to GT in comparison to age-matched fertile controls. To the best of our knowledge, this is the first study comparing OR and ovarian response between infertile and fertile Indian women.
Aim of the study
- To compare the OR and ovarian response to OS between fertile and infertile women of Indian ethnicity undergoing IVF-intracytoplasmic sperm injection (ICSI) at our ART center
- To assess the predictive value of OR markers age, AMH, and AFC in determining response to OS, measured by the number of oocytes retrieved.
| Materials and Methodology|| |
This was a prospective cohort study.
The study was conducted at a tertiary ART center.
Source of data
A total of 146 women undergoing IVF-ICSI at our fertility center between March 2017 and August 2017 were prospectively enrolled in this study. The study population included young women <35 years, with regular cycles having an AMH <5 ng/ml as measured by the Roche automated AMH assay and AFC < 25/25 measured using the 3D 8 MHz probe. Women with polycystic ovarian syndrome (PCOS), endometriosis, and history of unilateral oophorectomy and those on oral contraceptives were excluded from the study.
Women enrolled in the fertile group were parous oocyte donors while the infertile group included women who underwent IVF-ICSI as a part of their fertility treatment during the study period.
Informed consent was taken from each patient, and ethical clearance was obtained from the Independent Ethics committee (CTRI/2018/05/014207). A comprehensive clinical history and examination including body mass index (BMI) assessment were done for all the patients included in the study.
Anti-Mullerian hormone estimation
Two milliliters of blood was collected in the early follicular phase (cycle day 2-5) and circulating AMH levels were analyzed before the start of stimulation using the fully automated Elecsys® and Cobas e immunoassay analyzers (Roche Diagnostics GmbH, Germany). The Elecsys® immunoassay detects AMH in the range of 0.01–23 ng/ml (0.07–164 pmol/L) and requires 50 μl of serum or lithium-heparin plasma. It shows an excellent precision, linearity, and functional sensitivity in comparison to the manual AMH assays and has no interference in the results due to complement binding.
Antral follicle count assessment
AFC (the total number of follicles with a diameter between 2 and 9 mm in both ovaries) was assessed on day 2 or 3 of menstrual cycle using an 8 MHz transvaginal probe at our ART center.
In vitro fertilization-intracytoplasmic sperm injection protocol
Flexible GnRH antagonist protocol was followed for all the patients enrolled in the study. Dose of GTs was decided based on the patient's age, BMI, OR, AFC, and previous response. OS was done as per our institutional protocol with recombinant follicle-stimulating hormone (FSH, follitropin-alfa Gonal-f®, EMD Serono, Inc.,) for first 5 days followed by Menopur (highly purified HMG-Ferring Pharmaceutical Ltd.). Injection human chorionic GT 10,000 IU or triptorelin 0.2 mg s/c was given as the ovulation trigger and ovum pick up (OPU) performed 36 h later. The number of oocytes retrieved was noted in each group.
Age, AMH, AFC, BMI, and response to OS (number of oocytes retrieved) were then compared between the fertile and infertile group. We also sought to determine which of these factors was the best predictor of ovarian response to controlled OS.
Categorical variables were presented in number and percentage (%), and continuous variables were presented as mean ± standard deviation and median. Quantitative variables were compared using unpaired t- test/Mann–Whitney test (when the data sets were not normally distributed) between the two groups. Qualitative variables were correlated using Chi-Square test/Fisher's exact test. Univariate and multivariate logistic regression was used to assess the association of CLABSI with various parameters. P value was calculated using independent t-test and adjusted P values were calculated using ANOVA and a P < 0.05 was considered statistically significant. Data analysis was done using Statistical Package for the Social Sciences (SPSS) version 21.0. (IBM Corp., Armonk, NY, USA)
| Results|| |
The mean age of patients in the infertile group (n = 80) was 31.4 ± 2.6 while in the fertile group (n = 66) was 24.7 ± 2.0 (P < 0.001). The mean BMI was significantly higher in the infertile group 25.3 ± 3.1 in comparison with the fertile group 21.5 ± 3.4 (P < 0.001). We also found that the mean AMH (3.0 ± 1.2 vs. 4.1 ± 1.5) and AFC (13.0 ± 5.1 vs. 18.9 ± 16.6) were lower in the infertile group in comparison to the fertile group and this difference was statistically significant (P < 0.001) [Figure 1]. However, when adjusted for the differences in age and BMI, we found that there was no difference in the AMH (P = 0.298) and AFC (P = 0.302) between fertile and infertile women [Figure 2].
|Figure 1: Comparison of the demographic variables in the fertile and infertile groups|
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|Figure 2: Comparison of anti-Mullerian hormone and antral follicle count between the fertile and infertile groups|
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We also compared the number of oocytes retrieved in the two groups and found that the mean number of oocytes retrieved after adjusting for the demographic variables in the fertile group was 15.8 ± 7.5 while in the infertile group was 14.3 ± 7.5 (P = 0.510), suggesting no difference in ovarian response in fertile and infertile group having similar demographics and basal characteristics [Figure 3].
|Figure 3: Comparison of oocytes retrieved between fertile and infertile groups|
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Using linear regression analysis with adjusted regression, we found a statistically significant positive correlation between the number of oocytes retrieved and AMH (r = 2.11, P = 0.0001) Significant correlation was also seen between the number of oocytes retrieved and AFC (r = 0.08, P = 0.013). We also noted a negative correlation between the oocyte retrieved count and age, which was also significant (r = −0.450, P = 0.013). No correlation was identified between number of retrieved oocytes and BMI (r = −0.65, P = 0.520) [Figure 4].
|Figure 4: Correlation of age, anti-Mullerian hormone, antral follicle count, and number of oocytes retrieved|
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Using this univariate regression analysis, we deciphered that among the markers of OR studied, AMH had the strongest correlation with the number of oocytes retrieved (r = 2.11) in comparison to AFC (r = 0.08) and age (r = −0.45), suggesting AMH to be a superior predictor of response to OS [Figure 4].
| Discussion|| |
OR testing has been used to predict ovarian response in patients undergoing ART. Prediction of ovarian response allows for optimization of oocyte numbers and minimizing complications, by adjusting the dose of GT used for COS.,,,,,, A reliable and precise estimation of the patient's ovarian response facilitates individualization of COS protocols during ART. Age, ultrasound markers, and endocrine and dynamic tests have been proposed for predicting response to OS. Among these markers, AMH and AFC have been found to be the most precise and reliable.,,,
A cutoff age limit for depletion in OR has been taken as 35 years for the Caucasian population, and this cutoff age has been used globally for all ethnic groups. A variation in OR has been observed among ethnic populations.,,,,, Iglesias et al., 2014 in a study comparing OR between Indian and Spanish women concluded that Indian women had an earlier depletion of OR. Their study suggested that ovaries from Indian women aged 6 years earlier than those of Caucasian women. Purcell et al., 2007 reported that Asian women have a decreased clinical pregnancy rate (odds ratio 0.71, 95% confidence interval [CI] 0.64–0.80) and live birth rate (odds ratio 0.69, 95% CI 0.61–0.77) compared to their Caucasian counterparts. Jayaprakasan et al., 2014 confirmed that ethnicity is a major determinant of live birth following IVF treatment, with lower live birth rates being observed in Southeast Asian, Black African, and Middle-Eastern women than in White European women.
Higher prevalence of GTB has been proposed as a cause for the lower OR and its accelerated decline in Indian women. Jirge et al. in their study evaluated the effect of latent genital tuberculosis on OR in infertile Indian women. They reported a 15% reduction in AMH and AFC in women with latent GTB diagnosed by endometrial DNA polymerase chain reaction. They hypothesized that the presence of mycobacterial tuberculosis in the genital tract causes an accelerated decline in the ovarian follicle pool and leads to advanced ovarian aging.
Hvidman et al. compared the OR between infertile and fertile Caucasian women aged 20–39 years using AMH and AFC as markers of OR. They could not elucidate a difference in either the OR or the age-related decline in AMH and AFC between the two groups. They concluded that the frequent observation of patients with a poor response to COS in ART is related to an age-related decrease in OR. Greenwood et al. in 2017 also stated that women with unexplained infertility did not have a decreased OR as measured by AMH and AFC in comparison to age-matched community fertile controls.
We undertook a study to assess if there is an earlier depletion of OR in infertile Indian women compared to fertile one's given that GTB is a common cause of infertility in India. We also compared the ovarian response to COS between the two groups.
The results of our study revealed that there was no difference in the AMH (P = 0.298) and AFC (P = 0.302) between the fertile and infertile women when adjusted for differences in age and BMI. We also found that infertile and fertile women having similar demographics and basal characteristics show no difference in response to OS as estimated by the number of oocytes retrieved (15.8 ± 7 vs. 14.3 ± 7.5) (P = 0.510) which is in concordance with the above two studies. This would indicate that ovarian aging is similar between fertile and infertile Indian women and a poor reserve alone cannot be deemed as the cause of their infertility. Although basic evaluation of oocyte morphology was similar between groups, we cannot rule out that infertile women might be having a poorer oocyte quality irrespective of oocyte numbers as we could not perform any advanced techniques to evaluate oocyte quality.
Both AFC and AMH levels are good predictors of ovarian response during ART compared to other traditional measures, e.g., age and basal FSH level, and inhibin B.,,, Direct comparisons between AFC and AMH levels to evaluate which is the better predictor have thrown up controversial results. AFC, a sum of follicles measuring 2–10 mm on transvaginal ultrasound in the early follicular phase, has a good predictive value for the number of oocytes retrieved. It is easy to perform, is noninvasive, and provides immediate results, but it is subject to inter- and intra-observer variability and may overestimate the true number of FSH-sensitive follicles because of inclusion of nonviable atretic follicles of the same size. Its measurement is also inappropriate in obese women, women with large ovarian cysts, fibroids, or scars from previous surgeries. AMH, a member of the transforming growth factor-b superfamily, is produced by granulosa cells of preantral and small (<8 mm) antral follicles.,, It is involved in the regulation of follicular recruitment and reflects primordial follicle pool size. AMH estimation can be performed at any point during the cycle, it has low intra- and inter-cycle variability and can be measured across all age groups.,, It has been found to be a good predictor for ovarian response. Availability of the automated AMH assay has improved its sensitivity and reproducibility.,
A number of multicentric trials,,,,,,, have questioned the claim that these two biomarkers possess a similar ability to predict ovarian response [Figure 5] and [Figure 6]. Two large retrospective multicentric trial in both agonist Merit trial and antagonist cycles Megaset trial concluded that AMH was more strongly correlated with oocyte yield than AFC (Merit trial: r = 0.28 vs. r = 0.56, Megaset trial: r = 0.33 vs. r = 0.55). Our study is in corroboration with the above studies suggesting AMH be a better predictor of ovarian response in comparison to AFC (r = 2.11 vs. 0.08). None of our patients had any ART-related complications like ovarian hyperstimulation syndrome, which can be a sequel to inaccurate assessment of ovarian response. The possible reasons adding to the superiority of AMH to AFC in our study could be the use of fully automated AMH assay which is highly precise and reproducible and the uniformity of performing the assay in the early follicular phase of menstrual cycle in all our patients. We advocate the use of AMH to individualize the starting dose of GT, optimize response, and minimize complications.
|Figure 5: Performance of ovarian reserve markers in the prediction of ovarian response (Observational studies)|
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|Figure 6: Performance of ovarian reserve markers in the prediction of ovarian response (Multicentric trials)|
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| Conclusion|| |
Our results indicate that there is no difference in OR and ovarian response in fertile and infertile Indian having similar demographics and basal characteristics. In addition, amongst all markers of ORs, AMH is the strongest predictor of response to OS and should be used to calculating the starting dose of GTs.
Limitations of our study
The sample size of our study was small. We also were not able to do a more exhaustive assessment of oocyte morphology to see if there was a difference in oocyte quality between groups.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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