Women older than 40 years of age and those with elevated follicle-stimulating hormone levels differ in poor response rate and embryo quality in in vitro fertilization.

van Rooij IA, Bancsi LF, Broekmans FJ, Looman CW, Habbema JD, te Velde ER.

Department of Reproductive Medicine, Division of Obstetrics, Neonatology and Gynecology, University Medical Center Utrecht, The Netherlands. i.vanrooij@azu.nl

OBJECTIVE: To investigate whether IVF outcome of patients older than 40 years of age with basal FSH levels less than 15 IU/L differs from that in patients 40 years of age or younger with basal FSH levels of 15 IU/L or greater. DESIGN: Prospective observational study. SETTING: Tertiary academic fertility center. PATIENT(S): Women 41 years of age or older with basal FSH levels less than 15 IU/L (n = 50), and women 40 years of age or younger with elevated basal FSH levels (n = 36) undergoing their first IVF cycle. INTERVENTION(S): IVF treatment using a long suppression protocol with recombinant FSH at a fixed starting dose of 150 IU/L. MAIN OUTCOME MEASURE(S): Ovarian response, ongoing pregnancy rates, and implantation rates. RESULT(S): The high FSH group experienced more cycle cancellations due to absent follicular growth than did the high age group (31% vs. 8%). However, the high FSH group had better implantation rates per embryo (34% vs. 11%), higher ongoing rates per ET (40% vs.13%), and higher ongoing pregnancy rates per cycle (25% vs. 10%). In both groups, poor responders had lower pregnancy rates. CONCLUSION(S): The outcome of IVF differs between patients older than 40 years of age with normal FSH levels and relatively young patients with elevated FSH levels. This finding may have implications for the management of these patients.

ÜBERSETZUNG

Frauen über 40 Jahre und Frauen mit erhöhten FHS-Leveln unterscheiden sich in Bezug auf Poor-Response-Rate und 
Embryoqualität bei IVF  

Gegenstand: Untersuchung ob sich das Ergebnis einer IVF bei Patientinnen älter als 40 mit einem basalen FSH von unter 
15 IU/L von dem bei Patientinnen jünger als 40 und mit einem basalen FSH-Wert von 15 oder höher unterscheidet.
Art: Prospektive Beobachtungsstudie    
Patient(en): Frauen (41 Jahre und älter) mit basalen FSH-Werten von unter 15 IU/L und Frauen (40 Jahre oder jünger) 
mit erhöhten FSH-Werten unterzogen sich einer IVF.  
Intervention(en): IVF = Long Protokoll mit rec. FSH und einer festen Initialdosis von 150 UI/L.
Resultat: Die Gruppe der Frauen mit hohem FSH hatte mehr IVF-Abbrüche auf Grund der Abwesenheit von 
Follikelwachstum als die Gruppe der älteren Frauen ( 31% vs 8%)  
Jedoch hatte die Gruppe der Frauen mit hohem FSH besser Implantationsraten pro Embryo  
(35% vs 11%) und einen höheren Anteil weiterführender Schwangerschaften pro Transfer.   
(40% vs 13%)  sowie einen höheren Anteil weiterführender Schwangerschaften pro Zyklus  
(25% vs 10%). Der Ausgang einer IVF bei Frauen über 40 Jahren mit normalen FSH-Werten
und relativ jungen Patienten mit erhöhten FSH-Werten unterscheidet sich demnach. Diese  
Erkenntnis könnte Auswirkung auf den Umgang mit dieser Patientengruppe haben.

Was sagt uns das???
Poor Response ist nicht gleich Poor Response - oder: eine Schwalbe macht noch keinen Sommer bzw.
ein guter FSH Wert eine ältere Frau nicht schneller schwanger als eine jüngere mit schlechterem FSH-Wert

RESTLICHE ÜBERSETZUNGEN FOLGEN JE NACH LUST UND LAUNE

Reproductive outcome in patients with diminished ovarian reserve.

Levi AJ, Raynault MF, Bergh PA, Drews MR, Miller BT, Scott RT Jr.

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.

OBJECTIVE: To compare reproductive outcome between women with normal ovarian reserve and women with abnormal ovarian reserve. DESIGN: Retrospective. SETTING: Tertiary care center. PATIENT(S): Nine thousand eight hundred and two patients who had basal follicle-stimulating hormone (FSH) concentrations measured as part of an infertility evaluation. INTERVENTION(S): Monitoring of early pregnancy. MAIN OUTCOME MEASURE(S): Pregnancy loss rates, live birth rates. RESULT(S): Of 1,034 patients with diminished ovarian reserve (DOR) (FSH > or =14.2 IU/L), 28 (2.7%) conceived. Twenty of these pregnancies (20/28; 71.4%) were lost in the first trimester. Pregnancy loss rates in women with DOR were 57.1% in women <35 years old, 63.5% in women 35-40 years old, and 90.0% in women >40 years old. These rates of pregnancy loss were significantly higher compared to age-matched patients with normal ovarian reserve. 

CONCLUSIONS(S): Women with DOR have exceedingly high rates of pregnancy loss, regardless of age. Women with diminished ovarian reserve should be counseled that, in addition to a low probability of conception, live birth rates are poor.

DOR = Diminshed Ovarion Reserve = Eingeschränkte Eierstockreserve

Frauen mit DOR haben stark erhöhte Raten an FG, unbesehen ihres Alters. Frauen mit DOR sollten darüber auf-
geklärt werden, dass sowohl ihre Empfängnischancen als auch ihre Lebendgeburtrate gering ist.

 
Impact of repeated antral follicle counts on the prediction of poor ovarian response in women undergoing in vitro fertilization. (Bedeutung des wiederholten Zählens der
Antralfollikel in Bezug auf die Vorhersage einer schwache Eierstockreaktion bei Frauen
die eine IVF durchführen lassen)

Bancsi LF, Broekmans FJ, Looman CW, Habbema JD, te Velde ER.

Department of Reproductive Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. lbancsi@azu.nl

OBJECTIVE: To study the value of a single antral follicle count and the additional value of repeated counts in different cycles for the prediction of poor ovarian response in IVF. DESIGN: Prospective. SETTING: Tertiary fertility center. PATIENT(S): One hundred twenty women undergoing their first IVF cycle. INTERVENTION(S): Measurement of the number of antral follicles on cycle day 3 in two spontaneous cycles.Ovarian response. RESULT(S): A single antral follicle count is clearly predictive of poor ovarian response and there is good agreement between repeated measurements in subsequent cycles (area under the receiver operating characteristic curve [ROC(AUC)]; cycle 1: 0.87, cycle 2: 0.85). In a logistic regression analysis, information obtained after the second cycle contributed significantly to the prediction of poor response by the antral follicle count of the first cycle. The predictive accuracy of the highest of two counts (ROC(AUC) 0.89) was slightly better than that of each single count. The predictive model with the highest count yielded slightly higher values of specificity and positive predictive value. Sensitivity, negative predictive value, and error rates were slightly lower. CONCLUSION(S): A single antral follicle count is a good predictor of poor ovarian response in IVF. Although the impact of a second antral follicle count on ovarian response predictions in IVF is statistically significant, clinical relevance is very limited. Repeating an antral follicle count in a subsequent cycle is not recommended.

PMID: 14711542 [PubMed - in process]

In vitro fertilization in the older patient. (IVF bei älteren Patientinnen)

Derman SG, Seifer DB.

Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA. FertilMD@aol.com

In vitro fertilization (IVF) in the older patient presents a significant challenge to the clinician. Older IVF patients have higher cancellation rates, lower oocyte yields, lower pregnancy rates, and higher miscarriage rates, despite significant improvements in IVF success rates in the past decade. Markers of diminished ovarian reserve, including basal follicle-stimulating hormone and estradiol levels, clomiphene citrate challenge test, inhibin B, mullerian-inhibiting substance, ovarian volume, and antral follicle counts, can be useful in counseling patients. Alterations in the stimulation protocol, such as changing the gonadotropin or gonadotropin-releasing hormone (GnRH) agonist dose, use of the agonist flare or microdose flare protocols, or use of a GnRH antagonist have met with varying degrees of success in improving outcomes.

A prospective assessment of the predictive value of basal antral follicles in in vitro fertilization cycles. 

Frattarelli JL, Levi AJ, Miller BT, Segars JH.

Tripler Army Medical Center, Honolulu, Hawaii 96859-5000, USA. john.fratarelli@amedd.army.mil

OBJECTIVE: To determine the predictive value and define threshold values for basal antral follicle count in patients undergoing IVF. DESIGN: Prospective cohort analysis.Tertiary care center.Two hundred eighty-nine patients.Transvaginal ultrasonography before starting gonadotropin administration. MAIN OUTCOME MEASURES: Number of oocytes retrieved, basal hormone levels, and cycle outcomes. RESULTS: Pregnant patients had significantly more antral follicles (13.8 +/- 7.5 vs. 12.4 +/- 10.0). Patients in whom cycles were canceled had significantly fewer antral follicles (7.6 +/- 4.8 vs. 13.7 +/- 8.8). Antral follicle count significantly correlated with most prestimulation and poststimulation IVF variables. Threshold analysis demonstrated a lower pregnancy rate (23.5% vs. 57.6%) and a higher cancellation rate (41% vs. 6.4%) associated with having four or fewer antral follicles. 

CONCLUSION(S): The basal antral follicle count identified patients who responded poorly to IVF stimulation. Having four or fewer antral follicles was associated with a high cancellation rate (41%) and, in patients without a cancelled cycle, a low pregnancy rate (23%). However, no antral follicle count absolutely predicted pregnancy or cycle cancellation.

Das Zählen der basalen Antralfollikel konnte Patienten mit einer Low Response auf eine IVF-Stimulation identifizieren. Vier oder weniger Antralfollikel gingen mit einer hohen Abbruchrate einher (41%) und bei Patienten ohne Abbruch mit einer geringen Schwangerschaftsrate (23%). Jedoch konnte hierdurch nicht 100%ig ein Abbruch bzw. eine Schwangerschaft vorausgesagt werden. 

 
Antral follicle counts by transvaginal ultrasonography are related to age in women with proven natural fertility.

Scheffer GJ, Broekmans FJ, Dorland M, Habbema JD, Looman CW, te Velde ER.

Department of Obstetrics and Gynecology, University Hospital Utrecht, The Netherlands. G.J.Scheffer@dog.azu.nl

OBJECTIVE: To investigate the relation between reproductive age and ultrasound (US)-based follicle counts and the reproducibility of follicle counts in regularly cycling women with proven fertility. DESIGN: Prospective observational study. SETTING: Tertiary fertility center. PATIENT(S): Healthy female volunteers with proven fertility, recruited by advertisement in local newspapers. INTERVENTION(S): The number of antral follicles sized 2-10 mm and ovarian volume were estimated by transvaginal US in the early follicular phase of the menstrual cycle in 162 women. A subgroup of 81 women underwent transvaginal US at several times in three subsequent cycles. MAIN OUTCOME MEASURE(S): Antral follicle count and total ovarian volume. RESULT(S): Women aged 25-46 years (n = 162) were studied. The relation of age with the US indices was computed after natural log transformation. Antral follicle count showed the clearest correlation with age (R = -0.67). A biphasic linear model gave the best fit to the data. Before the age of 37 years, the antral follicle count showed a mean yearly decline of 4.8%, compared with 11.7% thereafter. The reproducibility of the antral follicle count in two subsequent cycles was moderate. 

CONCLUSION(S): The number of small antral follicles in both ovaries as measured by US is clearly related to reproductive age and could well reflect the size of the remaining primordial follicle pool.

            Ergebnis: Die Anzahl der kleinen Antralfollikel in beiden Eierstöcken per US gemessen ist ein sicherer Marker in
            Bezug auf das Fortpflanzungsalter und könnte gut die Grösse (Anzahl) des verbleibenden Pools der Primordialfollikel
            widerspiegeln

 
Reproductive aging and variability in the ovarian antral follicle count: application in the clinical setting.

Hansen KR, Morris JL, Thyer AC, Soules MR.

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Washington Medical Center, Seattle, Washington 98105, USA. krhansen@u.wahsington.edu

OBJECTIVE: To determine the extent of intercycle and interobserver variability in antral follicle (AF) count and their impact on stimulation quality in IVF. DESIGN: Prospective evaluation of the impact on AF count of GnRH agonist down-regulation and interobserver variability. Retrospective evaluation of intercycle variability in AF count. SETTING: University ART clinic. PATIENT(S): Twenty subjects were used to evaluate the effect of GnRH agonist down-regulation upon AF count; six of whom were used to evaluate interobserver variability. Fifty patients experiencing two or three cycles of IVF within a 1-year interval. INTERVENTION(S): Transvaginal ultrasound exams before and after down-regulation with a GnRH agonist. Videotaped day-3 transvaginal ultrasound exams. MAIN OUTCOME MEASURE(S): [1] Intercycle and interobserver variability in antral follicle count. [2] Oocytes retrieved, peak estradiol, gonadotropin dose, duration of stimulation and cancellation rates. RESULT(S): There is moderate intercycle and interobserver variability in AF counts. GnRH agonist down-regulation does not significantly change AF count. In infertility patients undergoing IVF, paired analysis between the low- and high-AF count cycles did not show a difference in quality of stimulation or cycle cancellation rates. CONCLUSIONS: Within an individual patient, higher AF count in a given cycle was not predictive of better stimulation compared with the case of a lower count cycle.  

 
Ovarian volume and antral follicle counts as indicators of menopausal status.

Flaws JA, Langenberg P, Babus JK, Hirshfield AN, Sharara FI.

Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore 21201, USA.

OBJECTIVE: Recent studies suggest that ovarian volume and antral follicle numbers may be sensitive, specific, and early indicators of menopausal status. The accuracy of these markers, however, has not been compared directly to more traditional markers [age and follicle-stimulating hormone (FSH) levels]. Thus, the purpose of this study was to test whether ovarian volume and antral follicle counts are more sensitive and specific markers of menopausal status than age or FSH levels. DESIGN: Premenopausal (n = 34) and postmenopausal (n = 25) women between 40 and 54 years old received a transvaginal ultrasound for determination of ovarian volume and antral follicle numbers, provided blood for measurement of FSH levels, and completed a questionnaire. FSH levels, age, ovarian volume, and antral follicle numbers were compared using t tests. Receiver operating characteristic curves were generated to evaluate the sensitivity and specificity of each marker. RESULTS: Postmenopausal women had significantly higher FSH levels (p < or = 0.0001), smaller ovarian volumes (p < or = 0.002), and fewer antral follicles (p < or = 0.002) than premenopausal women. Ovarian volume and antral follicle numbers had similar sensitivity (27.3-100%) and specificity (3.4-92.9%) in indicating postmenopausal status as FSH levels and age. CONCLUSION: These data suggest that ovarian volume and antral follicle numbers may be useful indicators of menopausal status.

 
Women with regular menstrual cycles and a poor response to ovarian hyperstimulation for in vitro fertilization exhibit follicular phase characteristics suggestive of ovarian aging.

Beckers NG, Macklon NS, Eijkemans MJ, Fauser BC.

Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Erasmus Medical Center, Rotterdam, The Netherlands.

OBJECTIVE: To investigate whether follicular phase characteristics associated with ovarian aging can be observed in women of normal reproductive age, who had previously shown a poor response to ovarian hyperstimulation for IVF. DESIGN: Observational, prospective study. SETTING: Tertiary fertility center. PATIENT(S): Eleven regularly cycling, ovulatory women, aged 29-40 years who previously presented with fewer than four dominant follicles after ovarian hyperstimulation for IVF. INTERVENTION(S): Frequent serum hormone assessments and transvaginal ultrasound during the follicular phase of a spontaneous, unstimulated cycle. MAIN OUTCOME MEASURE(S): Duration of the follicular phase; serum LH, FSH, E(2), P, inhibin A, and inhibin B levels; and number of antral follicles observed by ultrasound. Results were compared with the cycle characteristics of a reference population of 38 healthy normo-ovulatory women aged 20-36 years (as published elsewhere). RESULT(S): Poor responders had significantly fewer antral follicles than controls. Median FSH concentrations were significantly higher compared with controls, but the majority had FSH levels within the normal range. Follicular phase P levels were significantly higher in poor responders. Duration of the follicular phase, E(2), and inhibin A and inhibin B serum levels did not differ between poor responders and controls. CONCLUSION(S): Normo-ovulatory regularly cycling women with a previous poor response to ovarian hyperstimulation for IVF show follicular phase characteristics suggestive of ovarian aging.

PMID: 12137865 [PubMed - indexed for MEDLINE]  

 
Use of the total motile sperm count to predict total fertilization failure in in vitro fertilization.

Repping S, van Weert JM, Mol BW, de Vries JW, van der Veen F.

Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam, The Netherlands. s.repping@amc.uva.nl

OBJECTIVE: To evaluate the capacity of baseline characteristics and total motile sperm count (TMC) to predict total fertilization failure (TFF) in patients undergoing IVF. DESIGN: Retrospective cohort study. SETTING: University hospital. PATIENT(S): Eight hundred ninety-two couples with a total of 1,569 consecutive IVF cycles. INTERVENTION(S): Prewash and postwash TMC during fertility workup and at the time of ovum pickup (OPU). MAIN OUTCOME MEASURE(S): Analysis of logistic regression and the receiver operating characteristic curve were used to determine which variables could be used to predict TFF. RESULT(S): The area under the curve (AUC) for prewash TMC during fertility workup was 0.72, similar to a combination of pre- and postwash TMC. At the time of OPU, both pre- and postwash TMC had an AUC of 0.73. A model based on selected baseline characteristics (male age, number of IVF cycles, indication for IVF, and prewash TMC during fertility workup) had an AUC of 0.75. A model at the time of OPU, including the number of oocytes, had an AUC of 0.80. CONCLUSION(S): The use of both models, one before start of the IVF cycle and one at the time of OPU, allows an accurate prediction of the chance of TFF and is useful in counseling patients on whether to opt for IVF or ICSI.

PMID: 12095485 [PubMed - indexed for MEDLINE]  

 
A prospective study of predictive factors of ovarian response in 'standard' IVF/ICSI patients treated with recombinant FSH. A suggestion for a recombinant FSH dosage normogram.

Popovic-Todorovic B, Loft A, Lindhard A, Bangsboll S, Andersson AM, Andersen AN.

The Fertility Clinic, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark. drbiba@yahoo.com

BACKGROUND: The aim was to identify independent predictors of ovarian response to recombinant (r)FSH through a multiple regression analysis. METHODS: Prospective study including 145 'standard' patients treated with 150 IU/day of rFSH during their first IVF/ICSI cycle. Down-regulation was achieved with long agonist protocol. The following were examined as possible predictive factors: age, body mass index, cycle length, smoking status and on day 2-5: total ovarian volume, total number of antral follicles (<10 mm), total Doppler score of the ovarian stromal blood flow, serum FSH, LH, estradiol, inhibin B, and testosterone. RESULTS: Total number of antral follicles, total Doppler score, serum FSH, LH, estradiol, inhibin B, smoking status and cycle length were independent predictors of the number of aspirated follicles. The number of oocytes was predicted by the total number of antral follicles, total Doppler score, serum testosterone and smoking status. In bivariate linear regression analyses ovarian volume was a highly significant predictor of both the number of follicles (P < 0.001) and the number of oocytes (P < 0.001). CONCLUSIONS: Among 12 investigated possible predictive factors in 'standard' patients, the total number of antral follicles and ovarian stromal blood flow assessed by total Power Doppler score are the two most significant predictors of ovarian response. Suggestion for an rFSH dosage normogram is presented.

PMID: 12660271 [PubMed - indexed for MEDLINE]

 
The number of antral follicles in normal women with proven fertility is the best reflection of reproductive age.

Scheffer GJ, Broekmans FJ, Looman CW, Blankenstein M, Fauser BC, teJong FH, teVelde ER.

Department of Reproductive Medicine, Division of Perinatology and Gynecology, University Medical Center Utrecht, Heidelberglaan, The Netherlands. gabriellescheffer@hotmail.com

BACKGROUND: The purpose of this study was to compare the predictive capacity of several markers of reproductive age in normal women. METHODS: Healthy female volunteers (n = 162) aged 25-46 years with proven, normal fertility and regular menstrual cycles were recruited. In this selected group, chronological age was assumed to approximate reproductive age and, therefore, was taken as the proxy-variable for reproductive age. The number of antral follicles with 2-10 mm diameter, total ovarian volume, total follicular volume, mean follicular volume, and volume of either the smallest or largest ovary were estimated by transvaginal sonography of the ovaries. Serum levels of early follicular FSH, estradiol and inhibin B, as well as the response of estradiol and inhibin B to exogenous GnRH agonist administration (GAST), were also evaluated. RESULTS: Regression analysis revealed that the antral follicle number showed the highest correlation with age (r = -0.68, P = 0.001), and explained 46% of its variance. All other variables, except inhibin B, were moderately correlated with age. Responses of estradiol and inhibin B to the GnRH agonist were moderately correlated with age, but highly correlated with the number of antral follicles. CONCLUSIONS: It is concluded that the number of antral follicles has the closest association with chronological age in normal women with proven fertility. As stimulated estradiol and inhibin B clearly reflect the size of the antral follicle cohort, the GAST may be considered the second best single test to predict reproductive age.

PMID: 12660259 [PubMed - indexed for MEDLINE]

Ovarian reserve, female age and the chance for successful pregnancy.

Toner JP.

Atlanta Center for Reproductive Medicine, Woodstock, GA 30189, USA. jim.toner@acrm.com

Both quantitative and qualitative factors regarding egg production are strong influences on IVF outcome. Markers of ovarian reserve such as basal FSH, clomiphene citrate challenge test (CCCT), and antral follicle counts are good predictors of the quantity of eggs which can be induced to grow. However, the quality of those eggs seems better predicted by the age of the women. In women past age 40, current success rates are low overall, even in those who good ovarian reserve who make many eggs; at this age, quantity does not make up for quality. By contrast, young women with limited ovarian reserve can have good success rates despite their limited cohort of eggs, because the eggs themselves are of high potential; here quality matters more than quantity. The ramifications of these observations include the following: diminished ovarian reserve should not be used as an exclusionary criterion in young women, because overall they still have satisfactory pregnancy rates, though their risk of cancellation is increased. In women past age 40, normal ovarian reserve testing is not reassuring because even reduced egg quality is likely to limit the opportunity for successful pregnancy no matter how many eggs are available.

PMID: 14581882 [PubMed - in process]