Year : 2009 | Volume
: 2 | Issue : 2 | Page : 68--71
Antral follicle size in the downregulated cycle and its relation to in vitro fertilization outcome
Nabaneeta Padhy, M Latha, B Sathya, Thangam R Varma
Department of Reproductive Medicine, Institute of Reproductive Medicine, Madras Medical Mission, Chennai - 37, India
Flat No.-78, Victoria Gardens, Inner Ring Road, Koyambedu, Chennai - 107
Aim: In this study, we have attempted to relate the antral follicle size on day 3 of downregulation to the in vitro fertilization (IVF) outcome and hence test its predictive value for IVF outcome. Settings and Design: Teaching hospital, prospective double-blinded cohort study. The sonographer was blinded toward the patient profile whereas the follicular size on day 3 was concealed from the clinicians. Materials and Methods: Two hundred and twenty-eight patients undergoing the long protocol programme for IVF/intracytoplasmic sperm injection at the Institution are included in this study. The antral follicle size on day 3 of the downregulated cycle was measured for all patients and, based on the size, they were divided into three groups: Group I (0-3 mm), Group II (3-6 mm), and Group III (6-9 mm), Various outcome measures taken into account were amount and number of days of gonadotropin required, basal estradiol and follicle-stimulating hormone (FSH) level, zooming of follicles, and quality of oocytes. Statistical Analysis Used: Data were analyzed using the Graphpad software with a microsoft excel spread sheet. A P-value <0.05 (Fisher exact test) was taken to be significant. Multinomial regression tests were used as appropriate. Results: A significant number of follicles were in the 3-6 mm group whereas the population below 35 years constituted the majority. There was no significant difference in basal estradiol and FSH levels among the three groups. Accelerated growth of follicles (zooming) was significantly associated with bigger antral follicles ( P< 0.001) whereas poor quality oocytes were significantly higher in Group 1. Conclusion: The significant number of poor quality of oocytes produced by such follicles whereas zooming of follicles among the bigger antral follicle group suggest their accelerated development potential and hence the dose of gonadotropin should be adjusted accordingly, indicating evidence of intrinsic abnormality of folliculogenesis in very small follicles.
|How to cite this article:|
Padhy N, Latha M, Sathya B, Varma TR. Antral follicle size in the downregulated cycle and its relation to in vitro fertilization outcome.J Hum Reprod Sci 2009;2:68-71
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Padhy N, Latha M, Sathya B, Varma TR. Antral follicle size in the downregulated cycle and its relation to in vitro fertilization outcome. J Hum Reprod Sci [serial online] 2009 [cited 2021 Apr 12 ];2:68-71
Available from: https://www.jhrsonline.org/text.asp?2009/2/2/68/57225
There has been a continuous effort to provide an optimum environment for a successful controlled ovarian hyperstimulation (COH) programme. Various fields have been explored for this and during recent years there is increased interest in understanding the mechanism that regulates follicular growth during early gonadotropin-independent stages of development. Theoretically, every primordial follicle has the potential to mature and ovulate, but this seldom happens.  Folliculogenesis is a complex process in which there exists a delicate balance between recruitment and atresia of follicles. Transition from primordial to primary follicular stage does not show any change in the mean diameter of the oocyte, although there is an increase in the follicular diameter, indicating that this transition is a slow maturing rather than a growing process.  Although early folliculogenesis is independent of follicle-stimulating hormone (FSH) due to lack of receptors, FSH is required to protect these follicles from atresia. More so, by a direct or indirect action, pituitary hormones such as prolactin, TSH, and growth hormone act synergistically with luteinizing hormone (LH) and FSH to enhance the entry of non-growing follicles into the growth phase.  Hence, early folliculogenesis depends on various autocrine and paracrine mechanisms, which is difficult to interpret accurately. However, the size of the antral follicle does reflect the internal milieu and can predict dynamics of follicular growth. Studies have shown that during the later luteal phase the largest healthy follicles are between 2 and 5 mm in diameter.  Keeping this in view, we have made an effort to relate the antral follicular size on day 3 of the downregulated cycle to in vitro fertilization (IVF) outcome.
Materials and Methods
Two hundred and twenty-eight patients undergoing the long protocol programme for IVF/intracytoplasmic sperm injection at the Institute of Reproductive Medicine and Women's Health, Madras Medical Mission, are included, wherein eight cycles were cancelled due to poor response. The indications for IVF were unexplained infertility, tubal factor, endometriosis, poor ovarian reserve, and male factor infertility. All the patients were downregulated using Lupride (250 μg- 1 mg, depending on the basal LH) from day 21 of the previous cycle and were given an oral contraceptive pill for withdrawal bleed. Patients having persistent clear cysts were not included whereas those with endometriotic cysts were included in the study. After 10-12 days of gonadotropin-releasing hormone agonist administration, the day 3 follicular size was measured. The size of all antral follicles was measured and the patient was allocated into a group according to the mean follicular size. Based on the size, the patients were divided into three groups: Group I (0-3 mm), Group II (3-6 mm), and Group III (6-9 mm). Follicles larger than 9 mm were not included in the study group. All the patients were scanned using sonoline G 50 2D transvaginal probe of 7.5 MHz( siemens, germany) by a single observer to avoid observer bias. Various parameters like age and gynecological disorders like polycystic ovarian syndrome (PCOS) and endometriosis were correlated with the antral follicle size. Outcome measures taken into account were amount and number of days of gonadotropin required, basal estradiol and FSH level, zooming of follicles, and quality of oocytes. Zooming of follicles was defined as rapid growth in follicular size to reach 14 mm or more on day 6 of gonadotropin therapy or those follicles which were ready by day 8 of gonadotropin therapy. Various morphological criteria were used to define quality of oocytes at par with international standards.
Of 220 patients, 176 (80%)were less than 35 years of age and constituted the majority in all three groups, whereas 178 (80.6%) had primary subfertility. Male factor infertility accounted for 26% of the cases [Table 1]. 51.3% of the patients had 3-6 mm follicles, whereas only 18% had follicles less than 3 mm. Very small follicles as well as larger antral follicles were found in younger age groups, which signify that follicle size does not change with age [Table 2]. Majority of PCOS patients had larger antral follicles (PP= 0.06) [Figure 1]. There was no significant difference in basal estradiol and FSH levels among the three groups [Table 3]. Also, there was no difference in the amount of gonadotropin used, as this study was double blinded, and there was a difference in the median days of gonadotropin therapy (Group 1, P = 0.02). Accelerated growth of follicles (zooming) was significantly associated with bigger antral follicles ( P , However, smaller antral follicles constituted the majority of patients irrespective of age, which probably represents the endocrine reserve in the subfertile group.  In contrast, in PCOS patients, there is a cohort of heterogeneous follicles and the bigger antral follicles actually represent the endocrine reserve. Perhaps, the smaller follicles represent the proportion that has undergone premature arrest and hence is associated with follicular arrest in PCOS.  However, the developmental potential of oocytes derived from women with PCOS is normal and typically leads to a normal cumulative conception rate. , Pohl et al., in their series of 113 patients, found that patients with a higher number of follicles between 5 and 10 mm showed a significantly higher pregnancy rate. 
Zooming of follicles was significantly higher (P , 0.001) in Group III patients who had bigger antral follicles. There is emerging evidence for an intrinsic abnormality of folliculogenesis in PCOS that affects the very earliest, gonadotropin-independent stages of follicle development.  Although the cause of these early abnormalities are not yet clear, it could be attributed to abnormal serum concentration of FSH, which is suppressed below the threshold level during early follicular phase. Aberrant dynamics of follicle development during early stages leading to disproportionately more granulosa cells per oocyte in transitional and primary follicles may be the cause of such accelerated development.  Some authors have also proved that the granulosa cells cultured from follicles derived from anovulatory women with PCOS are hyperresponsive to FSH in terms of estradiol production. , It is clearly indicated in our study that zooming of follicles is significant high (P = 0.002)among Group I could be attributed to defective early folliculogenesis [Table 5]. Oocyte quality is determined by the follicular environment rather than by age factors.  As the very small antral follicles are not gonadotropin dependent and the number of granulosa cells are less, the response to COH is poor in such follicles and the mean duration of therapy is significantly high in this group.
Certainly, patients with follicles 6 mm in the downregulated cycle need more vigilant follow-up and survey. The quality of oocytes is influenced by the internal environment of the follicle, which is reflected in its size. In an era where the COH programme is being optimized in all respects, perhaps our study will add a parameter to predict IVF outcome. But, conclusions could be drawn only after following a larger series of patients.
|1||Salha O, Abusheikha N, Sharma V. Dynamics of human follicular growth and in vitro oocyte maturation. Hum Reprod Update 1998;4:816-32.|
|2||Gougeon A, Chainy GB. Morphometric studies of small follicles in ovaries of women at different ages. J Reprod Fertil 1987;81:433-42.|
|3||Hendriks DJ, Broekmans FJ, Bancsi LF, de Jong FH, Looman CW, Te Velde ER. Repeated clomiphene citrate challenge testing in the prediction of outcome in IVF: A comparison with basal markers for ovarian reserve. Hum Reprod 2005;20:163-9.|
|4||Gougeon A, Lefèvre B. Evolution of the diameters of the largest healthy and atretic follicles during the human menstrual cycle. J Reprod Fertil 1983;69:497-502.|
|5||MHaadsma ML, Bukman A, Groen H, Roeloffzen EM, Groenewoud ER, Heineman MJ, Hoek A. The number of small antral follicles (2-6 mm. determines the outcome of endocrine ovarian reserve tests in a subfertile population. Hum Reprod 2007;22:1925-31. |
|6||Khairy M, Clough A, El-Toukhy T, Coomarasamy A, Khalaf Y. Antral follicle count at down-regulation and prediction of poor ovarian response. Reprod Biomed Online 2008;17:4.|
|7||Dewailly D, Catteau-Jonard S, Reyss AC, Leroy M, Pigny P. Oligoanovulation with polycystic ovaries but not overt hyperandrogenism. J Clin Endocrinol Metab 2006;91:3922-7.|
|8||Hardy K, Robinson FM, Paraschos T, Wicks R, Franks S, Winston RM. Normal development and metabolic activity of preimplantation embryos in vitro from patients with polycystic ovaries. Hum Reprod 1995;10:2125-35.|
|9||Heijnen EM, Eijkemans MJ, Hughes EG, Laven JS, Macklon NS, Fauser BC. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update 2006;12:13-21.|
|10||Pöhl M, Hohlagschwandtner M, Obruca A, Poschalko G, Weigert M, Feichtinger W. Number and size of antral follicles as predictive factors in vitro fertilization and embryo transfer. J Assist Reprod Genet 2000;17:315-8.|
|11||Franks S. Polycystic ovary syndrome: a changing perspective. Clin Endocrinol (Oxf) 1989;31:87-120.|
|12||Erickson GF, Magoffin DA, Garzo VG, Cheung AP, Chang RJ. Granulosa cells of polycystic ovaries: are they normal or abnormal? Hum Reprod 1992;7:293-9.|
|13||Mason HD, Willis DS, Beard RW, Winston RM, Margara R, Franks S. Estradiol production by granulosa cells of normal and polycystic ovaries: Relationship to menstrual cycle history and concentrations of gonadotropins and sex steroids in follicular fluid. J Clin Endocrinol Metab 1994;79:1355-60.|
|14||Smitz JE, Cortvrindt RG. The earliest stages of folliculogenesis in vitro. Reproduction 2002;123:185-202.|