Poor ovarian response in patients younger than 35 years: is it also a qualitative decline in ovarian function?

Human Fertility, September 2009; 12(3): 160–165 Poor ovarian response in patients younger than 35 years: Is it also aqualitative decline in ovarian function? ´ VIO FIGUEIRA1, DANIELA PAES ALMEIDA FERREIRA BRAGA1,2, MARCI´LIO NICHI3, CAMILA MADASCHI1, LUCIANA SEMIA ASSUMPTO IACONELLI JR1, & EDSON BORGES JR1,2 1Fertility-Assisted Fertilization Center, Sa˜o Paulo, SP, Brazil, 2Sapientiae Institute, Educational and Research Center inAssisted Reproduction, Sa˜o Paulo, SP, Brazil, and 3Department of Animal Reproduction, Faculty of Veterinary Medicine andAnimal Science (FMVZ), University of Sa To investigate whether poor response to controlled ovarian stimulation (COS) is due to a qualitative decline in This retrospective cohort study included 436 patients younger than 35-years old, undergoing COS for intracytoplasmic sperm injection (ICSI). Patients with four or fewer MII oocytes after COS (poor-responder group, PR,n ¼ 52) were age-matched with normoresponder patients (NR, n ¼ 364).
Results.
Although similar duration of stimulation (10.5 + 0.4 and 9.3 + 0.8 days; p ¼ 0.1358), increased doses of gonadotrophins (2510 + 865 and 2253 + 572 IU; p ¼ 0.0061) were used in the PR. The results show a increased chance ofcycle ending of PR (PR: 26.9% and NR: 3.1%; p 5 0.0001). Although the lower total number of oocytes retrieved (2.4 + 1.4and 16.2 + 9.3; p 5 0.0001), equal rate of fertilization (70.2% and 72.0%, p ¼ 0.1190) and high quality embryos wereobtained (50.0% and 45.2%; p ¼ 0.4895), resulting in similar implantation (14.5% and 19.7%; p ¼ 0.2246) and abortion (10.0% and 15.4%; p ¼ 1.00) rates, respectively. A trend towards increased pregnancy rate per embryo transfer in NR groupwas noted (PR: 26.3% and NR: 42.2%; p ¼ 0.0818).
Conclusions.
Low ovarian response could be associated mainly with a quantitative rather than a qualitative decline in ovarian function. Therefore, even if the ovarian response to stimulation is low, patients aged 35 years should process to oocyteretrieval.
Keywords: ICSI, ovarian stimulation, oocyte retrieval 2002; Ubaldi et al., 2005). It has been estimated that among patients undergoing IVF treatment the Women have a finite number of germ cells whose prevalence of poor ovarian response is 9–24% (Keay Hum Fertil (Camb) Downloaded from informahealthcare.com by FACULDADE DE ODONTOLOGIA - USP number progressively diminishes through an irrever- sible process of follicular atresia. The rate of Garcia et al. (1983) first describe a poor responder follicular attrition is not constant but rather follows as the patient with peak estradiol (E2) levels 5 300 an exponential pattern (Faddy et al., 1992). Pre- pg/mL after a standard stimulation with hMG. Since mature reduction of ovarian follicle number has been demonstrated to significantly affect the success of brought into clinical use to define and categorize assisted reproduction techniques (ART), despite the poor responders without consensus. Poor responders chronological women age (Templeton et al., 1996).
have been defined on the basis of mature oocytes A dynamic assessment of the ovarian reserve could (Lashen et al., 1999), elevated early follicular phase be associated with the way a woman’s ovaries of FSH peak (Esposito et al., 2002), number of basal respond to stimulation with gonadotrophins during antral follicle (Loverro et al., 2003), number of in vitro fertilization (IVF) treatment (Nikolaou et al., follicle at the end of ovarian stimulation (Ulug et al., Correspondence: Edson Borges Jr., M.D., Ph.D., Fertility-Assisted Fertilization Center, Av. Brigadeiro Luiz Antoˆnio 4545, Sa˜o Paulo, SP, Brazil 01402-001.
Fax: þ(55-11)-3885-9858. E-mail: [email protected] ISSN 1464-7273 print/ISSN 1742-8149 online Ó British Fertility SocietyDOI: 10.1080/14647270902942928 Poor ovarian response in patients younger than 35 years and the study was approved by local institutional Several factors could be associated with reduced ovarian response to controlled ovarian stimulation(COS) in either older or younger patients with early COS was achieved by long pituitary down regulation ovarian ageing (Nikolaou et al., 2002). Young using a gonadotropin-releasing hormone agonist assisted reproduction patients with diminished ovar- ian reserve is a disappointing issue in reproductive Franc¸aise des Laboratoires, Paris, France) followed medicine. Those patients are usually stimulated with high doses of gonadotrophins and a small number of (Gonal-F1, Serono, Geneve, Switzerland). The follicles develop (Tarlatzis et al., 2003). The course of treatment often reaches a point where the dilemma starting on day 4 of gonadotropin administration.
is whether to carry on or cancel a cycle (Ulug et al., When adequate follicular growth and serum estradiol levels were observed, recombinant human chorionic Some investigators have proposed that oocyte gonadotrophin (r-hCG, OvidrelTM, Serono, Geneve, quality is established during fetal life, and oocytes Switzerland) was administered to trigger final folli- that are less susceptible to non-disjunction are cular maturation. Oocytes were collected 35 hours ovulated first, leaving poor quality oocytes to be after hCG administration by transvaginal ultrasound ovulated later in life (Gougeon, 1996). For this reason, poor prognosis for IVF would be related to Oocytes were stored in human tubal cultured decline in ovarian follicle number than to age. On the medium (HTF, Irvine Scientific, Santa Ana, USA) other hand, experimental data in women demon- supplemented with 10% Human Synthetic Albumin strated that an increased frequency of meiotic non- (HSA, Irvine Scientific, Santa Ana, USA) covered disjunction occur at female ovary as time goes by.
with oil (OvoilTM, Vitrolife, Kungsbacka, Sweden) at This is the mechanism responsible for the majority of 378C in 6% CO2 for 5 h, before cumulus cell aneuploidies in early embryos suggesting that ovarian removal. Cumulus cells were removed from the reserve is a better predictor of oocyte production oocytes by placement HEPES buffered-medium capacity than oocyte quality, whereas age affects containing hyaluronidade (80IU/mL Irvine Scienti- oocyte quality (Hanoch et al., 1998; Eldar-Geva fic, Santa Ana, USA). The remaining cumulus cells surrounding were then removed by gently pipetting Therefore, this study summarizes the results of with a hand draw Pasteur pipette (Humagen Fertility assisted reproduction treatment in poor responder patients younger than 35 years compared with thoseage-matched normoresponder (NR). The purpose is to evaluate whether the poor response to COS is dueto a reduced ovarian reserve (reflected by doses of Intracytoplasmatic sperm injection was performed in MII oocytes according to the technique described by number of eggs collected and cycle cancellation rate) Palermo et al. (1992). Oocytes were transferred into rather than poor oocyte quality (reflected by ICSI the micro-injection dish, prepared with drops of HEPES-buffered HTF (Irvine Scientific, Santa Ana,USA) covered under oil and placed on a heated stage Hum Fertil (Camb) Downloaded from informahealthcare.com by FACULDADE DE ODONTOLOGIA - USP of an inverted microscope. Approximately 16 h after ICSI, fertilization was confirmed by the presence oftwo pronuclei and the extrusion of the second polar body. Embryos were kept in a 50 mL drop of HTF Data of intracytoplasmic sperm injection (ICSI) medium supplemented with 10% HAS under oil, in cycles performed in 416 patients younger than 35 a humidified atmosphere of 5% CO2 in air, at 378C, years old were included in this retrospective cohort study. All cases of surgically retrieved sperm were Embryo transfer was performed on the second or excluded from the study. Patients who produced four third day of development. For each couple, one to or less MII oocytes (poor-responder, PR group, n ¼ 52) after COS were age matched with NRpatients in which five or more oocytes were retrieved (NR group, n ¼ 364). A written informed consentwas obtained, in which patients agreed to share the Serum b-hCG levels were assessed for the first time outcomes of their own cycles for research purposes, 12 days after replacement of the embryos. Clinical R. de Ca´ssia Sa´vio Figueira et al.
pregnancy was defined when a transvaginal ultra- sound scan, performed 3–4 weeks after embryo The range of maternal age was 25–35 years.
transfer, revealed the presence of a gestational sac.
Although similar duration of gonadotrophin stimula- To calculate the implantation rate, the number of tion between the two groups; significantly increased gestational sacs was divided by the number of doses of gonadotrophins were used in the PR group.
embryos transferred. Miscarriage was defined as the Oestradiol concentration on day of hCG and oocyte spontaneous abortion before 20 weeks’ gestation.
yield were significantly lower in PR group.
The oocyte retrieval rate was significantly lower in the PR group, however, the MII oocyte rate wasfound to be similar (Table I). Normal fertilization The two groups were compared with regard to: (i) rate was found to be similar between the two groups.
age; (ii) total gonadotrophin dose (IU); (iii) duration Although the higher cycle ending without embryo of gonadotrophin stimulation (days); (iv) oestradiol transfer and the lower number of embryos trans- concentration on day of hCG (pg/mL); (v) oocyte ferred (1.9 + 1.2 versus 3.1 + 1.1; p 5 0.0001), poor yield (no. of retrieved oocytes / no. follicles); (vi) responder patients presented similar percentage metaphase II oocyte rate (MII oocyte / total number of high quality embryos on the third day of of retrieved oocyte); (vii) percentage of high quality embryos on the third day of development (no. of high A trend towards increased pregnancy rate per quality embryos / no. of fertilized MII oocytes); (viii) embryo transfer in NR group was also noted, but did normal fertilization (no. of zygote showing two not reach statistical significance. On the other hand, clearly distinct pronuclei/no. of injected oocytes); implantation rate between the two groups were not (ix) cycle cancellation (no. of embryo transfers/no. of significantly different. Likewise, no difference was initiated cycles); (x) pregnancy rate; (xi) implanta- found between the two groups for ongoing preg- nancy rate and abortion rate. The results of ICSI High quality embryos were defined as those cycles outcomes of poor responder patients are showing 6–8 cells on the third day of development; less than 15% fragmentation; symmetric blasto-meres; absence of multinucleation and absence ofzona pellucida dysmorphism.
Despite the reasonable percentage of women under- going infertility treatment that respond poorly to the Results were expressed as mean + standard devia- usual gonadotrophin stimulation protocol, there is tion for numeric variables, while proportions (%) no uniformity in the definition of the poor response.
were used for categorical variables. Mean values were The number of developed follicles and/or number of compared by Student’s t parametric test or Mann– oocytes retrieved after an ovarian stimulation proto- Whitney non-parametric test, accordingly Gaussian col are, hierarchically, two of the most important distribution. Proportions were compared by the Chi- criteria for defining poor ovarian response.
squared or Fisher exact test, only when expected Previous reports have proposed different numbers frequency was five or fewer. Results were considered of MII retrieved oocytes after ovarian stimulation to to be significant at the 5% critical level ( p 5 0.05).
define a poor responder patient and it ranges from Data analysis was carried out using GraphPad Prism less than three to less than five retrieved oocytes Hum Fertil (Camb) Downloaded from informahealthcare.com by FACULDADE DE ODONTOLOGIA - USP (Rombauts et al., 1998; Surrey et al., 1998). With Table I. Stimulation cycles characteristics in a group of poor responder patients younger than 35 years (PR group) compared with those age-matched normoresponders (NR group).
No. of retrieved oocytes/No. follicles (%) MII oocyte / total number of retrieved oocyte (%) Values expressed as mean + SD, unless otherwise noted.
*Statistical Mann–Whitney test.
{Student’s t-test.
Poor ovarian response in patients younger than 35 years Table II. Intracytoplasmic sperm injection cycles outcomes in a the embryos development until the third day (i.e., group of poor responder patients younger than 35 years (PR 72 h after ICSI), when embryonic genome activation group) compared with those age-matched normoresponders.
should have occurred. Together with the above cited studies, the fertilization and high quality embryo’srates observed in our study suggest that in young patients the poor ovarian response may be rather due to a decreased ovarian reserve than a poor oocyte The reason why, in spite of similar fertilization, high-quality embryos and implantation rates, a trend toward increased pregnancy rate per embryo transfer was observed in the NR group, may be explained bythe higher number of available embryos. In fact, the number of embryos transferred was significantly lower in PR group and the selection for transfer was limited. Nevertheless, implantation rate in PRgroup was found to be not statistically different from respect to our study, we choose to assign patients those of NR patients indicating that the low oocyte with less than four MII retrieved oocytes in the poor yield has no impact upon the biological capacity of those eggs. In addition, our results show that young In this present study, poor responders’ patients poor responder patients have a significantly increased used significantly higher gonadotrophins doses when chance of the cycle ending without embryo transfer.
compared with age-matched NRs stimulated during However, the similarity in the implantation rate, similar interval of days. Ovarian stimulation proto- among the groups, strengthens the argument against cols are employed to stimulated multifollicular cancel the cycles of young poor responders. In growth and to allow the retrieval of multiple oocytes.
addition, once the pregnancy is achieved, similar In most cases, when submitted to COS protocols, abortion rates were observed in PR patients when patients with a low number of antral follicles often receive a higher initial dose of gonadotrophins. In During follicular development, the vast majority of addition, when the standard dose of gonadotrophins follicles will go to atresia either by apoptosis or fails to induce a proper multifollicular growth, the necrosis at some stage of development. The criteria expected clinical approach is to increase the dose for determining the number and selection of follicles (Surrey & Schoolcraft, 2000). As a result, the total which are removed from the pool become less dose of gonadotrophins is significantly higher in poor stringent with increasing age. Assuming that follicle atresia plays a role in determining the overall quality matched NRs stimulated during similar interval of of follicles which reach the final stage of develop- days. There is, however, increasing evidence that ment, this implies a reduced quality control of excessive ovary stimulation may have detrimental follicles in older women (van Rooij et al., 2003). A effects on oocyte and embryo quality and endome- diminished ovarian reserve in young women could be trial receptivity (Karande et al., 1990; Simon et al., caused by a genetically regulated mechanism of 1995; Land et al. 1996; Bourgain & Devroey, 2003; higher intrinsic rate of atresia. Previous ovary surgery (Nargund & Bromhan, 1995), severe endometriosis Hum Fertil (Camb) Downloaded from informahealthcare.com by FACULDADE DE ODONTOLOGIA - USP Although the lower total number of oocytes (Wardle et al., 1985), post infectious adhesions retrieved, poor responder patients have similar MII (Keay et al., 1998), chemotherapy (Nargund & oocytes ratio, fertilization, high-quality embryos and Bromhan 1995) and smoking (Sharara et al., 1994) implantation rates. Even though it has been de- are known factors that can also affect the ovarian scribed that the quality of sperm plays a key role reserve (De Sutter & Dhont, 2003). Therefore, during fertilization (Swann et al., 2006; Saunders oocytes of poor responders may be of good quality et al., 2007), investigation of oocytes remaining although they are the last oocytes available from the unfertilized revealed that missing or disturbed oocyte ovarian pool. In addition, young PR patients could activation may be the main cause of fertilization be protected from some age-related deleterious failure after ICSI (Sousa & Tesarik, 1994). Further- effects (Hanoch et al., 1998; El-Toukhy et al., 2002).
more, the expression of the embryonic genome, Another possibility is that some patients have had a which is a combination of the sperm and oocyte destructive process that left behind fewer follicles contribution, starts between the four- and eight-cell but the same proportion of good quality oocytes stage of human embryo development (Tesarik et al., (Check, 1999; Check et al., 2002). In addition, 1986, 1988). Therefore, the oocyte is essential for besides diminished ovarian reserve, several possible R. de Ca´ssia Sa´vio Figueira et al.
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