The polymorphism Ala307Thr of the Follicle Stimulating Hormone Receptor (FSHR) gene is associated with different doses of recombinant FSH received during IVF/ICSI treatment
Felipe DieamantCláudia G. PetersenL.D. VagniniBruna PetersenJuliana RicciAndreia NicolettiCamila ZamaraAntônio Hélio OlianiJ.B.A. OliveiraJ.G. Franco
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Follicle-stimulating hormone (FSH) is essential for folliculogenesis, acting through the follicle-stimulating hormone receptor (FSHR) that is present on the membrane of granulosa cells. Polymorphisms in the FSHR gene may lead to an altered pattern of receptor expression on the cell surface or to changes in affinity for FSH. The aim of this prospective study was to detect any association between the follicle-stimulating hormone receptor (FSHR) gene Ala307Thr polymorphism (rs6165) and ovarian reserve, ovarian response or clinical results in IVF/ICSI treatment.This prospective cohort study included 450 women who underwent IVF/ICSI cycles. DNA was extracted from peripheral blood, and the Ala307Thr FSHR polymorphism (rs6165) was genotyped using the TaqMan SNP genotyping assay. Participants were divided into three groups according to their Ala307Thr FSHR genotype: Thr/Thr (n:141), Thr/Ala (n=213) and Ala/Ala (n=96). The results were tested for associations with age, anti-Mullerian hormone (AMH) levels, antral follicle count (AFC), total dose of r-FSH, follicle size, number of retrieved oocytes, and clinical outcome of IVF/ICSI cycles. The statistical analyses were performed using Fisher's exact test and the Kruskal‒Wallis test.An association between the genotype of the FSHR (Ala307Thr) polymorphism and the dose of r-FSH was observed. Patients with the Ala/Ala genotype received a higher r-FSH dose than patients with the Ala/Thr (p=0.0002) and Thr/Thr (p=0.02) genotypes. No other correlation was observed.The Ala/Ala genotype was associated with the use of higher doses of recombinant FSH (r-FSH), suggesting that homozygosis of this allelic variant (Ala) provides lower sensitivity to r-FSH.Keywords:
Follicle-stimulating hormone receptor
Antral follicle
Anti-Müllerian hormone
Ovarian Reserve
Abstract STUDY QUESTION Does anti-Müllerian hormone (AMH) induce preantral follicle atresia in mice? SUMMARY ANSWER The present findings suggest that AMH-mediated follicle atresia only occurs in early follicles before they become sensitive to FSH. WHAT IS KNOWN ALREADY Most prior studies have investigated the ability of AMH to inhibit primordial follicle activation. Our previous study showed that AMH-overexpressing mice had fewer preantral follicles than expected after accounting for primordial follicle inhibition but the reason for this was not determined. STUDY DESIGN, SIZE, DURATION Cross-sectional—control versus transgenic/knockout mouse studies were carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS Studies were conducted on female wild-type (Amh+/+), AMH-knockout (Amh−/−) and AMH overexpressing (Thy1.2-AMHTg/0) mice on a C57Bl/6J background (age: 42–120 days). The follicle counts were conducted for primordial, transitioning, primary, secondary and antral follicles in Amh−/− and Amh+/+ mice. After confirming that follicle development speeds were identical (proliferating cell nuclear antigen immunohistochemistry), the ratio of follicles surviving beyond each stage of folliculogenesis was determined in both genotypes. Evidence for increased rates of preantral follicle atresia was assessed by active caspase-3 immunohistochemistry in wild-type and Thy1.2-AMHTg/0 mice. MAIN RESULTS AND THE ROLE OF CHANCE Amh −/− mice at 100–120 days of age had lower primordial follicle counts but higher primordial follicle activation rates compared to Amh+/+ mice. These counteracting effects led to equivalent numbers of primordial follicles transitioning to the primary stage in Amh+/+ and Amh−/− mice. Despite this, Amh+/+ mice had fewer primary, secondary, small antral and medium antral follicles than Amh−/− mice indicating differing rates of developing follicle atresia between genotypes. Cleaved caspase-3 immunohistochemistry in Thy1.2-AMHTg/0 ovaries revealed high rates of granulosa cell and oocyte apoptosis in late primary/early secondary follicles of Thy1.2-AMHTg/0 mice. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION The findings were shown only in one species and additional research will be required to determine generalizability to other species. WIDER IMPLICATIONS OF THE FINDINGS This study is consistent with prior studies showing that Amh−/− mice have increased primordial follicle activation but these new findings demonstrate that AMH-mediated preantral follicle atresia is a predominant cause of the increased small antral follicle counts in Amh−/− mice. This suggests that the role of AMH is not to conserve the ovarian reserve to prolong fertility, but instead to prevent the antral follicle pool from becoming too large. While this study may demonstrate a new function for AMH, the biological purpose of this function requires further investigation, particularly in mono-ovulatory species. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the Health Research Council of New Zealand and the University of Otago. No competing interests to declare.
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Objectives: This study aims to find the correlation between anti mullerian hormone (AMH) and follicle stimulating hormone (FSH) and to observe the above mentioned hormones' relation with antral follicle count (AFC) in patients with primary infertility.Methodology: This is a cross-sectional correlation study in which 60 patients with primary infertility meeting inclusion criteria, attending infertility clinic in ESIC MC PGIMSR, Rajajinagar between January 2017 and June 2018 were enrolled by simple random sampling.Detailed menstrual, obstetric, coital and medical history was obtained.On the third day of the spontaneous cycle, all patients were investigated with a transvaginal scan to assess the number of antral follicles and a fasting venous blood sample was obtained for the measurement of serum AMH and serum basal FSH level.Results: Basal serum FSH shows a moderately strong negative correlation with antral follicle count (AFC) (r=0.65;p=<0.001); and a strong negative correlation with anti mullerian hormone (AMH) (r=0.69 and p=<0.001).However, the strongest correlation between a biochemical marker and biophysical marker of ovarian reserve is between anti mullerian hormone (AMH) and antral follicle count (AFC) with a very strong positive correlation with a correlation co-efficient r=0.89 (p=<0.001).Conclusion: Serum AMH best correlates with the antral follicle count.Antral follicle counts although an efficient test to detect ovarian reserve is uncomfortable for the patient as it has to be done during menstrual flow.Serum AMH with minimal intracycle and intercycle variation is a more convenient marker to assess ovarian reserve while it maintains the accuracy of AFC.
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Anti-mullerian hormone(AMH)is produced in the ovary by the granulose cells(GC) surrounding preantral and small antral follicles stage.AMH can be used for assessing ovarian reserve,predicting peri-menopausal period,and involving folliculogenesis.It also can be used for evaluating the effect of ART.It has been suggested that AMH would inhibit the initiation of primordial follicle growth and FSH-induced follicle growth.In recent years,the correlation between AMH and PCOS became important.It maybe help to explain pathogenesy and assess diagnostic efficacy and therapeutic efficacy in PCOS patient.
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Reproductive aging is the decline of female fertility with age. It is caused by the decrease in the number of growing follicles, resulting from primordial follicle pool depletion. Recently, we have shown that anti-Müllerian hormone (AMH) is produced by growing follicles, and studies in women indicate that serum AMH levels decrease with age and correlate with antral follicle count. However, whether serum AMH levels correlate directly with the size of the primordial follicle pool cannot be determined in women. In this work, we describe studies in mice in which we determined the dynamics of ovarian follicles during aging. Furthermore, we describe the development of a mouse AMH ELISA, allowing us to measure AMH levels in mice, for the first time. We observed that serum AMH levels decline with increasing age, whereas expression of AMH in individual growing follicles, studied by immunohistochemistry, did not change with age. Thus, the decline in serum AMH correlates directly with the decline in the number of growing follicles (r = 0.86, P < 0.0001). We observed that the number of growing follicles correlated with the number of primordial follicles (r = 0.93, P < 0.0001). Similarly, we found a strong correlation between AMH levels and number of primordial follicles (r = 0.83, P < 0.0001). In conclusion, serum AMH levels reflect the size of the primordial follicle pool in aging mice. Therefore, AMH is an excellent marker to assess the quantitative aspect of ovarian reserve, which may be useful for women at risk for early ovarian aging such as survivors of childhood cancers.
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The effects of estradiol, FSH and LH on ovarian follicular development and granulosa cell differentiation were examined in the immature rat hypophysectomized on day 24 of age. Administration of estradiol to hypophysectomized rats for 4 days stimulated the growth of large preantral follicles with a concomitant 1.5-fold increase in FSH receptor content and a 4-fold decrease in LH receptor content in the granulosa cells. When highly purified hFSH was administered alone, receptor content for FSH increased progressively for 4 days while receptor for LH remained essentially unchanged. However, when rats were pretreated with estradiol, the response of follicles to FSH was markedly enhanced as indicated by the appearance of large, antral follicles and elevated receptor content for both FSH and LH. Receptor content for FSH increased markedly in response to hFSH following only one day of estradiol pretreatment, while receptor content for LH increased most rapidly in response to hFSH after 3 days of estradiol pretreatment. LH administered to rats possessing large preovulatory follicles caused luteinization of granulosa cells and a marked decline in receptor content for both gonadotropins within 24 h. Receptor content remained low even 48 h after LH administration when granulosa cells were fully luteinized. These results indicated that follicular development and granulosa cell differentiation are dependent on steroid-protein hormone regulation of hormone specific receptors.
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Background: Follicle development is dependent on the interrelationship of many hormones, such as follicle stimulating hormone (FSH) and anti-Mόllerian hormone (AMH). Ovary-specific expression in granulosa cells of growing nonselected follicles makes AMH an ideal marker for the size of the ovarian follicle pool. Thus, the objective was to study the variability of AMH during menstrual cycle and relationship between serum AMH and FSH in infertile women and to observe their relation with antral follicle count (AFC) as to determine, which is a better predictor of infertility. Materials and Methods: This study includes 75 infertile women in aged 30-40 years. Blood samples were taken at day three for serum AMH and FSH levels, and AFC was done. AMH was estimated again on day 14 of the menstrual cycle. Results: Mean serum AMH and FSH were 1.18 ± 0.57 ng/ml and 9.09 ± 2.51 mIU/ml on day three of menstrual cycle. Mean AMH levels on day fourteen was 1.12 ± 0.53 ng/ml, which was not significantly different from day three AMH level. There was a significant inverse relationship between serum AMH and FSH concentration (r = −0.488, P < 0.001). Furthermore, there was a positive correlation between AMH and AFC (r = 0.641, P < 0.001). Conclusion: There was a significant inverse correlation between serum AMH and FSH levels in infertile women and we consider AMH, a better predictor of ovarian reserve as it is relatively stable throughout the cycle. Furthermore, there is was positive correlation between AMH and AFC, denoting reduction of AMH levels in serum is the first indication of a decline in the follicular reserve.
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Follicle-stimulating hormone (FSH) is essential for folliculogenesis, acting through the follicle-stimulating hormone receptor (FSHR) that is present on the membrane of granulosa cells. Polymorphisms in the FSHR gene may lead to an altered pattern of receptor expression on the cell surface or to changes in affinity for FSH. The aim of this prospective study was to detect any association between the follicle-stimulating hormone receptor (FSHR) gene Ala307Thr polymorphism (rs6165) and ovarian reserve, ovarian response or clinical results in IVF/ICSI treatment.This prospective cohort study included 450 women who underwent IVF/ICSI cycles. DNA was extracted from peripheral blood, and the Ala307Thr FSHR polymorphism (rs6165) was genotyped using the TaqMan SNP genotyping assay. Participants were divided into three groups according to their Ala307Thr FSHR genotype: Thr/Thr (n:141), Thr/Ala (n=213) and Ala/Ala (n=96). The results were tested for associations with age, anti-Mullerian hormone (AMH) levels, antral follicle count (AFC), total dose of r-FSH, follicle size, number of retrieved oocytes, and clinical outcome of IVF/ICSI cycles. The statistical analyses were performed using Fisher's exact test and the Kruskal‒Wallis test.An association between the genotype of the FSHR (Ala307Thr) polymorphism and the dose of r-FSH was observed. Patients with the Ala/Ala genotype received a higher r-FSH dose than patients with the Ala/Thr (p=0.0002) and Thr/Thr (p=0.02) genotypes. No other correlation was observed.The Ala/Ala genotype was associated with the use of higher doses of recombinant FSH (r-FSH), suggesting that homozygosis of this allelic variant (Ala) provides lower sensitivity to r-FSH.
Follicle-stimulating hormone receptor
Antral follicle
Anti-Müllerian hormone
Ovarian Reserve
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Citations (2)