Objective
The objective of the study was to determine the fecundity of young women (<35 years) with an elevated day 3 follicle stimulating hormone (FSH) undergoing gonadotropin-stimulation/intrauterine insemination.
Study Design
This was a retrospective study. The study was conducted at an academic fertility center. A total of 1396 gonadotropin stimulation/intrauterine insemination cycles from 563 women were stratified by day 3 FSH levels (<10 vs ≥10 U/L) and outcomes were compared. Gonadotropin dose, treatment duration, peak estradiol (E 2 ), number of preovulatory follicles (total, large, and medium size), E 2 /follicle, endometrial thickness, spontaneous abortion, clinical and multiple pregnancy rates were measured.
The statistics included a Student t test, a χ 2 , regression, and a discrete survival analysis.
Results
An elevated day 3 FSH was found in 10.2% of the women, despite favorable age (31.9 ± 2.5 years). Women with a day 3 FSH of 10 U/L or greater when compared with women with a normal day 3 level required significantly more medication (1058.9 ± 1106.0 vs 632.7 ± 477.5 IU, P < .0001) were triggered a day earlier (10.6 ± 2.4 vs 11.5 ± 2.9 days, P = .0006) and had E 2 levels (on the day of and the day prior to human chorionic gonadotropin administration) that were significantly higher (529.5 ± 244.3 vs 450.0 ± 244.2 and 359.6 ± 141.7 vs 306.8 ± 160.9 pg/mL, respectively, P < .05). Clinical pregnancy rates were comparable among the groups (14.6 vs 14%, respectively, P > .05). Spontaneous abortion and multiple pregnancy rates were higher among women with an FSH of 10U/L or greater but not significantly so (27.8% vs 12.0%, 22.2% vs 13.8% for FSH of ≥10 vs FSH < or >10 U/L, P > .05).
Conclusion
Women younger than 35 years with an elevated day 3 FSH, when treated aggressively with gonadotropins have pregnancy rates comparable with those of women with a normal baseline FSH. To achieve this outcome, they need higher doses of medication to stimulate the production of a larger preovulatory follicular cohort.
In the setting of infertility, accurate determination of ovarian reserve is extremely important because the information is used by clinicians to determine eligibility and protocols for fertility treatments and to properly counsel couples about the probability of success of the proposed therapies. Several ovarian reserve tests are available and include measurement of day 3 follicle-stimulating hormone (FSH) and estradiol (E 2 ), basal inhibin-B and antimullerian hormone (AMH) levels, the clomiphene citrate (CC) challenge test, and the ultrasonographic evaluation of antral follicle counts (AFC) and ovarian volume. Despite the plethora of available ovarian response biomarkers and the evidence suggesting that AFC and AMH correlate better with true ovarian reserve (histologically confirmed ovarian primordial follicle number) than day 3 FSH does, the latter is widely available and often used as either the first-line or the only test in ovarian reserve evaluation.
Elevation in basal FSH levels is thought to reflect ovarian aging and is associated, at least in older women undergoing in vitro fertilization (IVF), with poor ovarian response and low pregnancy rates, with numerous studies also suggesting that decreased ovarian reserve (DOR) is associated with a higher chance of fetal loss and chromosomal abnormalities in the conceptus.
Because most of the studies evaluating the association between measures of ovarian reserve and reproductive outcomes have been performed in older patients undergoing aggressive assisted reproduction technology treatments, it is difficult to counsel younger women with elevated basal FSH levels about their appropriate treatment options and expected success rates. Furthermore, basal FSH levels predict more accurately the size of the remaining oocyte pool and not necessarily its quality (the latter declines as age advances and biological damage to the oocyte accumulates). This potentially accounts for the more favorable reproductive outcome of younger poor responders compared with that of their older counterparts.
The purpose of the present study was to evaluate the prognostic significance of elevated day 3 FSH levels on the outcome of gonadotropin stimulation (GS)/intrauterine insemination (IUI) cycles in women younger than 35 years. GS/IUI cycles with normal basal FSH levels (<10 U/L) were compared with cycles characterized by elevated FSH levels (≥10 U/L). Thus, we sought to provide the treating physicians with a tool to properly counsel younger patients (with elevated basal FSH levels) regarding less aggressive treatment options such as GS/IUI.
Materials and Methods
The study was approved by the Massachusetts General Hospital Institutional Review Board. All IUI cycles (January 2004 through July 2010) from women younger than 35 years were retrospectively reviewed, and 1396 GS/IUI cycles were identified and further analyzed. Of these, 143 cycles were from women with a basal FSH of 10 U/L or greater.
At the time of treatment initiation, all participants had completed a standard infertility work-up (as described elsewhere). Recombinant FSH or human menopausal gonadotropins was started on the third day after a spontaneous or a progesterone-induced menstrual bleed. Response to gonadotropins was monitored and dose adjusted, as needed. Ovulation was triggered with recombinant human chorionic gonadotropin (hCG; Ovidrel; Serono, Norwell, MA), and 35-36 hours later, the IUI was performed.
Once stimulation started, cycles were cancelled either for overresponse (more than 5 preovulatory follicles) or for no response. Pregnancy was defined as clinical when at least 1 gestational sac was visualized on ultrasound 3-4 weeks after the IUI.
Outcome measures included the following: total gonadotropin dose, duration of gonadotropin stimulation, peak E 2 , number of preovulatory follicles (total, large [≥15 mm], and medium size [13-15 mm]), E 2 per follicle produced, spontaneous abortion (SAB), and clinical and multiple pregnancy rates.
Statistics
Means or geometric means between groups were compared using a Student t test or 1-way analysis of variance as appropriate for continuous variables, and χ 2 , and Fisher exact tests were used to compare categorical data. Multivariable models for associations between day 3 FSH and the outcomes of interest, adjusted for age and body mass index (BMI), were constructed.
For continuous outcomes, linear mixed-effects models were used to account for correlations between cycles within patient. Several variables (gonadotropin dose, peak E 2 variables, and peak E 2 variables divided by number of follicles) were skewed and transformed by the natural logarithm prior to inclusion in the models. The association of elevated day 3 FSH on the number of large, medium, and total follicles was assessed using generalized estimating equations (GEE) poisson regression models. A logistic GEE model was used to model whether a pregnancy was achieved as well as the odds of a multiple pregnancy or SAB.
Finally, because a live birth occurred only a maximum of 1 time per patient, a discrete survival model that adjusted for the cycle was used to calculate odds ratios for achieving a live birth in relation to elevated day 3 FSH. Values of P < .05 were considered statistically significant.
Results
During the study period, 2681 insemination cycles were performed. In 1396 cycles, gonadotropins were used either alone (n = 1391) or in combination with CC (n = 5). Five hundred and two women (89.2%) with a basal FSH less than 10 U/L contributed 1253 cycles (89.8%) and 61 women (10.8%) with an FSH of 10 U/L or greater contributed 143 cycles (10.2%). Overall, GS/IUI cycles represented 57% and 71.8% of the insemination cycles performed among women with normal and elevated basal FSH levels, respectively ( P = .0001).
Table 1 summarizes the demographic characteristics stratified by the day 3 FSH. The mean age, day 3 FSH, and BMI of the study participants were 31.9 ± 2.5 years, 7.3 ± 2.7 U/L, and 23.7 ± 4.4 kg/m 2 , respectively. The age distribution was as follows: 235, 293, and 868 cycles were from women younger than 30 years, 30 years or less to 32 years or less, and between 32 years or less and 35 years or less, respectively.
| Characteristic | Group | P value | |
|---|---|---|---|
| Day 3 FSH <10 (n = 1253) | Day 3 FSH ≥10 (n = 143) | ||
| Age, y (Mean ± SD) | 31.8 ± 2.5 | 33.1 ± 2.3 | < .0001 |
| BMI, kg/m 2 (Mean ± SD) | 23.8 ± 4.5 | 23.2 ± 4.9 | .12 |
| Day 3 FSH, U/L (Mean ± SD) | 6.6 ± 1.7 | 13.1 ± 3.4 | < .0001 |
| Infertility diagnosis | |||
| Number of cycles, n (%) | |||
| Idiopathic | 492 (39.3) | 25 (17.5) | < .0001 |
| Ovulatory dysfunction | 128 (10.2) | 4 (2.8) | .002 |
| Endometriosis | 46 (3.7) | 1 (0.7) | .08 |
| PCOS | 157 (12.5) | 3 (2.1) | < .0001 |
| Male factor | 179 (14.3) | 6 (4.2) | .0002 |
| Tubal factor | 43 (3.4) | 1 (0.7) | .08 |
| Uterine factor | 8 (0.6) | 0 (0.00) | 1.0 |
| DES exposure | 0 (0.0) | 0 (0.00) | 1.0 |
| Combined factor | 165 (13.2) | 44 (30.8) | < .0001 |
| DOR | 29 (2.3) | 59 (41.3) | < .0001 |
| Other | 6 (0.5) | 0 (0.00) | .5 |
Women with an elevated day 3 FSH were slightly older than the ones with a normal day 3 value ( Table 1 ) and were less likely to have received CC in the past (14.7 vs 49.1%, respectively, P < .01). The most common infertility diagnosis among the former group was DOR, followed by combined factors, and idiopathic infertility, whereas in the latter, the most prevalent diagnosis was idiopathic infertility, followed by male and combined factors ( P < .01 for all comparisons, Table 1 ).
Women with a day 3 FSH of 10 U/L or greater required significantly more medication and were triggered a day earlier than women with normal day 3 levels. E 2 on the day of and the day prior to hCG trigger was significantly higher in women with an elevated day 3 FSH ( Table 2 ).
| Characteristic | Group | P value | |
|---|---|---|---|
| Day 3 FSH <10 (n = 1253) | Day 3 FSH ≥10 (n = 143) | ||
| Total FSH dose | |||
| Mean ± SD | 632.7 ± 477.5 | 1058.9 ± 1106.0 | < .0001 |
| Median (25th, 75th) | 525 (375, 725) | 700 (525, 1050) | |
| Peak E 2 (on hCG day) | |||
| Mean ± SD | 450.03 ± 244.2 | 529.5 ± 244.3 | .0125 |
| Median (25th, 75th) | 404 (255, 597) | 495(346, 694) | |
| Peak E 2 (day prior to hCG) | |||
| Mean ± SD | 306.8 ± 160.9 | 359.6 ± 141.7 | .017 |
| Median (25th, 75th) | 272 (188, 387) | 341 (276, 445) | |
| Day of hCG trigger | |||
| Mean ± SD | 11.5 ± 2.9 | 10.6 ± 2.4 | .0006 |
| Median (25th, 75th) | 11(10, 13) | 10 (9, 12) | |
| Total motile sperm (million) | |||
| Mean ± SD | 52.9 ± 60.2 | 44.8 ± 46.4 | .14 |
| Median (25th, 75th) | 34.9 (15.3, 65.7) | 32.2 (1.8, 58.2) | |
| Endometrial thickness, mm | |||
| (Mean ± SD) | 8.5 ± 2.2 | 8.5 ± 2.1 | .8 |
| Pregnancy rate/completed cycle, % (n) | 14.6 (167) | 14.0 (18) | 1.0 |
| Pregnancies/cycle order, % | |||
| First cycle | 40.1 | 55.6 | .22 |
| Second cycle | 28.7 | 16.7 | .40 |
| Third cycle | 28.1 | 11.1 | .16 |
| Fourth cycle | 3.0 | 16.7 | .03 |
| SAB rate, % (n) | 12.0 (20/167) | 27.8 (5/18) | .074 |
| Multiple pregnancy rate, % (n) | 13.8 (23/167) | 22.2 (4/18) | .30 |
On average, women with a normal day 3 FSH produced 1.8 ± 0.95 total follicles per cycle, and those with an elevated FSH produced 2.1 ± 0.96 follicles ( P = .0004). The percentage of patients who developed 1 follicle only in response to gonadotropins was significantly higher in the normal FSH group with significantly more patients in the high FSH group producing 2-3 follicles (46.9 vs 33.6%; P = .003, and 45.2 vs 59.2%; P = .002, respectively).
Using a GEE model adjusted for age and BMI, we noted that women with an elevated day 3 FSH produced more total follicles than women with a normal value (parameter estimate [PE], 0.14; 95% confidence interval [CI], 0.04–0.24; P = .007) primarily because they produced a higher number of medium size follicles (PE, 0.32; 95% CI, 0.12–0.53; P = .002; Figure 1 , A-C). However, using a linear mixed-effects model adjusted for age and BMI, we noted that women with an elevated day 3 FSH produced fewer total follicles per given FSH dose (PE, –0.8; 95% CI, –1.5 to –0.13; P = .02).
With regard to the outcome of the cycle, there was no difference in the number of pregnancies achieved. The clinical pregnancy rate per cycle was 14.6% and 14.0% for FSH less than 10 and FSH 10.0 U/L or greater, respectively (14.1% and 13.8%, respectively, P = 1.0, when limiting the analysis to ovulatory women only). Sixty-nine percent and 72% of the pregnancies were achieved by the second cycle ( P = 1.0), whereas 32.4% and 29% of the women attempting to conceive eventually did ( P = .7).
Adjusting for age and BMI and using GEE to calculate the odds for pregnancy and discrete survival analysis to calculate the odds for live birth, we noted no difference between the 2 groups (odds ratio [OR], 1.2; 95% CI, 0.6–1.7, P = .9, and OR, 0.9; 95% CI, 0.4–1.8; P = .7, respectively; Figure 2 , A). There were more miscarriages and multiple pregnancies among the women with an elevated FSH, but differences were not significant (27.8% vs 12%, P = .074; 22.2% vs 13.8%, P = .3 for FSH of ≥10.0 vs <10 U/L, respectively). However, the former SAB rate was higher than expected for women younger than 35 years. Adjusting for age and BMI and using GEE to calculate the odds for SAB and discrete survival analysis to calculate the odds for multiple pregnancy, we noted no significant difference between the 2 groups (OR, 2.0; 95% CI, 0.5,–7.8; P = .3, and OR, 3.0; 95% CI, 0.7–13.2; P = .15, respectively; Figure 2 , B).
Cancellation rates were similar (8.4% vs 9.1% for FSH less than 10 vs FSH 10 U/L or greater, respectively, P = .57), although more cycles were cancelled for overresponse in the former (36.4% vs 0.0%) and for low or no response in the latter (20.0% vs 69.2%, respectively, P = .0005). In the latter, the vast majority of cancellations (92%) occurred in women older than 33 years of age. Furthermore, women with an elevated FSH whose cycles were cancelled were older and heavier than those with a normal FSH and cancelled cycles (33.5 ± 1.6 vs 31.0 ± 2.9 years; P = .003, 26.6 ± 7.5 vs 23.7.0 ± 4.3 kg/m 2 ; P = .037, respectively). In the group of women with an FSH of 10 U/L or greater, cancelled cycles were characterized by a significantly higher basal FSH and BMI than those completed and leading to an IUI (FSH: 15.9 ± 4.7 vs 12.8 ± 3.2 U/L, P = .0016; BMI: 26.6 ± 7.5 vs 22.8 ± 4.4 kg/m 2 , P = .007).
Day 3 FSH levels did not correlate with either the peak E 2 levels or with the E 2 level (both on the day of and the day prior to hCG trigger) per produced preovulatory follicle.
Among patients with an elevated day 3 FSH, those who conceived did not differ in age, day 3 FSH, medication dose, total number of follicles, and number of follicles greater than 15 mm from the ones that did not conceive. However, most pregnancies (89%) were seen in women with an FSH less than 14.0 U/L (representing 74.2% of the elevated basal FSH cycles). Furthermore, in the latter subgroup, pregnancy rates were higher and SAB rates lower (16.0% vs 5.4%, and 25.0% vs 50.0%, for FSH less than 14.0 vs 14.0 U/L or greater, respectively), but numbers were too small to reach meaningful statistical conclusions.
Among women with an elevated basal FSH, more cancellations were noted in the subgroup of women with an FSH of 14.0 U/L or greater, but the difference did not reach statistical significance (16.2% vs 6.6%, P = .1).
Among patients who conceived, the mean number of cycles per patient required to achieve a clinical pregnancy did not differ significantly between normal (1.95 ± 0.93) and elevated day 3 FSH women (1.94 ± 1.3).
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