1Department of Clinical and Lab Operations, Indira IVF Hospital Ltd, Udaipur, India
2Department of Reproductive Medicine, Indira IVF Hospital Ltd, Udaipur, India
3Department of Embryology, Indira IVF Hospital Ltd, Udaipur, India
4Department of Reproductive Medicine, Indira IVF Hospital Ltd, Patna, India
5Department of Reproductive Medicine, Indira IVF Hospital Ltd, Delhi, India
6Department of Reproductive Medicine, Indira IVF Hospital Ltd, Kolkata, India
7Department of Reproductive Medicine, Indira IVF Hospital Ltd, Allahabad, India
8Department of Biostatics, Indira IVF Hospital Ltd, Udaipur, India
9Department of Research and Publication, Indira IVF Hospital Limited, Udaipur, India.
Abstract
Daily recombinant FSH (rFSH) administration remains the standard for controlled ovarian stimulation in IVF/ICSI, yet it increases treatment burden, cost, and discomfort for patients. Evidence supporting reduced frequency dosing, particularly among women with normal ovarian reserve, is limited. This pilot randomized controlled trial evaluated the feasibility of an alternate day rFSH protocol after an initial five day daily phase. Sixty women were randomized to either continued daily rFSH or alternate day dosing once a leading follicle reached ≥14 mm. Baseline characteristics and ovarian reserve mark-ers were comparable across groups. The alternate day protocol significantly reduced total gonadotropin use and resulted in lower trigger day progesterone, while maintaining similar oocyte yield, MII oocyte rates, and embryological outcomes. Trends toward higher estradiol levels and more embryos were observed in the alternate day arm. These findings suggest that alternate day rFSH dosing is a feasible, patient friendly, and potentially cost saving strategy without compromising stimulation or laboratory outcomes. Larger studies are needed to validate its clinical utility.
Background and Objective
Recombinant follicle-stimulating hormone (rFSH) exhibits a prolonged half-life and sustained biological activity [1], raising the possibility that alternate-day administration could provide adequate follicular stimulation without compromising clinical outcomes. If proven non-inferior to daily dosing, this strategy may reduce injection burden, lower medication costs, and improve patient comfort while maintaining efficacy in terms of oocyte yield, fertilization, and pregnancy rates [2-4]. This pilot study aimed to compare daily versus alternate-day rFSH dosing in women with normal ovarian reserve undergoing IVF/ICSI, addressing a gap in current literature and exploring the feasibility of a more patient-friendly stimulation protocol.
Material and Method
This was a single-center, prospective, pilot randomized controlled trial conducted over a six-month period at a tertiary fertility care center. The aim was to compare the efficacy of alternate-day versus daily recombinant FSH (rFSH) dosing protocols in women undergoing controlled ovarian stimulation (COS) for IVF/ICSI. A total of 60 women were enrolled and randomized equally (1:1) into two study arms: Arm 1: Conventional daily rFSH dosing and Arm 2: Alternate-day rFSH dosing from stimulation day 6 onward. Participants were randomized using a computer-generated sequence to one of two treatment arms. The starting dose of rFSH was individualized based on age, BMI, AFC, and AMH levels. All patients received daily rFSH for the first five days of stimulation. In Arm 1 (Daily Dosing), rFSH was continued daily until the day of the ovulation trigger. In Arm 2 (Alternate-Day Dosing), patients continued rFSH daily until at least one leading follicle reached ≥14 mm in diameter, after which the same dose was administered on alternate days until the trigger. The remainder of the IVF protocol, including antagonist administration, trigger criteria, oocyte retrieval, fertilization (IVF or ICSI), embryo culture, and embryo transfer, followed the institution’s standard clinical practice. Embryo transfers were performed on Day 5. The study was approved by the institutional ethical committee.
Results
Among the 60 women included in this analysis, the median age was 31 years (IQR: 28.0–36.5; mean ± SD: 31.75 ± 4.78; range: 22–40), and the median BMI was 25.6 kg/m² (IQR: 23.32–28.92; mean ± SD: 25.68 ± 3.18; range: 18.5–29.9), reflecting a predominantly young population with BMI val-ues spanning normal to overweight categories. Indicators of ovarian reserve were moderate, with a median AMH of 2.54 ng/mL (IQR: 1.94–3.36; mean ± SD: 2.71 ± 1.15; range: 0.72–5.86) and a median day 2 AFC of 13 (IQR: 10–16.75; mean ± SD: 13.51 ± 5.02; range: 4–34). The median daily gonadotropin dose was 262.5 IU (IQR: 225–300; mean ± SD: 266.67 ± 59.60; range: 150–450), administered over a median of 10 days (IQR: 10–11; mean ± SD: 10.53 ± 1.26; range: 8–14), resulting in a median cumulative dose of 3000 IU (IQR: 2250–3375; mean ± SD: 2946.61 ± 843.02; range: 1350–4950). On the trigger day, estradiol (E2) levels exhibited substantial variability and right-skew (median: 2680.5 pg/mL; IQR: 1384.5–5077.5; mean ± SD: 3809.33 ± 3430.53; range: 403–13,800), while progesterone (P4) remained relatively low (median: 1.00 ng/ mL; IQR: 0.70–1.42; mean ± SD: 1.19 ± 0.74; range: 0.30– 4.20). Table 1 illustrates a comparison among stimulation characteristics of alternative day with conventional protocols, in most of the parameters are comparable, except for the total dose of gonadotropin and days of trigger P4. Figure 1 shows that, compared with the conventional-dose protocol, the alternate-dose protocol [5] achieved significantly lower total gonadotropin exposure and lower trigger-day progesterone, while maintaining comparable oocyte yield, oocyte maturity (MII rate), and other outcomes. There were trends toward higher trigger-day estradiol and more embryos formed in the alternate-dose arm [6].
|
DFI
|
(n)
|
Mean ± SD
|
Median (IQR)
|
95 % CI (Mean)
|
P
|
|
Female Age
|
|
Conventional Dose
|
30
|
32.86 ± 5.13
|
34.50 (27.75, 38.00)
|
(30.94, 34.78)
|
0.076*
|
|
Alternate Dose
|
30
|
30.63 ± 4.18
|
30.50 (28.00, 33.00)
|
(29.06, 32.19)
|
|
Female BMI
|
|
Conventional Dose
|
30
|
25.77 ± 3.01
|
25.75 (22.57, 28.62)
|
(24.65, 26.90)
|
0.864*
|
|
Alternate Dose
|
30
|
25.58 ± 3.38
|
25.25 (23.37, 29.32)
|
(24.31, 26.84)
|
|
AMH
|
|
Conventional Dose
|
30
|
2.07 ± 1.22
|
2.52 (2.05, 3.13)
|
(2.24, 3.16)
|
0.819*
|
|
Alternate Dose
|
30
|
2.72 ± 1.09
|
2.61 (1.79, 3.52)
|
(2.31, 3.13)
|
|
Day-2 AFC
|
|
Conventional Dose
|
30
|
13.26 ± 5.48
|
12.00 (10.00, 16.00)
|
(11.21, 15.31)
|
0.436*
|
|
Alternate Dose
|
30
|
13.76 ± 4.58
|
14.00 (10.00, 17.25)
|
(12.05, 15.47)
|
|
Daily Dose of Gonadotropin
|
|
Conventional Dose
|
30
|
262.50 ± 67.51
|
225.00 (225.00, 300.00)
|
(237.28, 287.71)
|
0.301*
|
|
Alternate Dose
|
30
|
270.83 ± 51.31
|
300.00 (225.00, 300.00)
|
(251.67, 289.99)
|
|
Total Days of Ovarian Stimulation
|
|
Conventional Dose
|
30
|
10.70 ± 1.29
|
11.00 (10.00, 11.25)
|
(10.21, 11.18)
|
0.294*
|
|
Alternate Dose
|
30
|
10.36 ± 1.24
|
10.00 (10.00, 11.00)
|
(9.90, 10.83)
|
|
Total Dose of Gonadotropin
|
|
Conventional Dose
|
30
|
3170.00 ± 892.41
|
3300.00 (2418.00,3843.00)
|
(2836.76, 3503.23)
|
0.036*
|
|
Alternate Dose
|
30
|
2715.51 ± 733.85
|
2700.00 (2212.50, 3187.50)
|
(2436.37, 2994.66)
|
|
Trigger Day E2
|
|
Conventional Dose
|
30
|
3019.63 ± 2563.77
|
2200.00 (1038.00, 4313.00)
|
(2062.03, 3976.69)
|
0.098*
|
|
Alternate Dose
|
30
|
4599.30 ± 4009.84
|
2859.50 (1796.25, 6394.00)
|
(3101.99, 6096.60)
|
|
Trigger Day P4
|
|
Conventional Dose
|
30
|
1.39 ± 0.82
|
1.15 (0.80, 1.87)
|
(1.08, 1.70)
|
0.036*
|
|
Alternate Dose
|
30
|
0.98 ± 0.59
|
0.95 (0.50, 1.38)
|
(0.76, 1.20)
|
|
Number of Oocyte Expected
|
|
Conventional Dose
|
30
|
10.13 ± 4.38
|
10.50 (6.00, 14.00)
|
(8.49, 11.77)
|
0.213*
|
|
Alternate Dose
|
30
|
12.03 ± 5.22
|
12.50 (8.00, 15.25)
|
(10.08, 13.98)
|
|
Number of Oocyte Retrieved
|
|
Conventional Dose
|
30
|
9.20 ± 5.41
|
8.00 (4.00, 14.25)
|
(7.18, 11.21)
|
0.189*
|
|
Alternate Dose
|
30
|
10.53 ± 4.03
|
11.00 (6.75, 14.00)
|
(9.02, 12.03)
|
|
MII
|
|
Conventional Dose
|
30
|
6.10 ± 3.76
|
5.00 (3.00, 9.00)
|
(4.69, 7.50)
|
0.190*
|
|
Alternate Dose
|
30
|
7.00 ± 3.09
|
7.00 (4.00, 9.00)
|
(5.84, 8.15)
|
|
MII Rate
|
|
Conventional Dose
|
30
|
66.90 ± 15.77
|
67.00 (55.25, 75.00)
|
(61.00, 72.79)
|
0.923*
|
|
Alternate Dose
|
30
|
66.46 ± 13.47
|
68.00 (56.75, 73.50)
|
(61.43, 71.49)
|
|
No of Embryo Formed
|
|
Conventional Dose
|
30
|
1.73 ± 1.52
|
1.50 (1.00, 2.25)
|
(1.16, 2.30)
|
0.052*
|
|
Alternate Dose
|
30
|
2.30 ± 1.31
|
2.00(2.00, 3.00)
|
(1.80, 2.79)
|
SD: Standard Deviation, IQR: Interquartile Range, CI: Confidence Interval, P: P Value, P<0.05: Statistical Significance, *: Mann-Whitney U test.
Table 1: Comparison of Conventional vs Alternate Day Dose
Conclusion
Alternate-day rFSH dosing after an initial daily phase appears non-inferior to conventional daily administration for controlled ovarian stimulation in women with normal ovarian reserve. It appears to be a feasible and potentially cost-saving alternative to daily dosing in IVF/ICSI cycles. It may reduce patient burden without compromising treatment outcomes, but further evidence is needed to support broader clinical adoption.
Declaration
Funding Statement:
There is no funding available.
Disclosure:
There is no conflict of interest among the authors.
Attestation Statement:
• The subjects in this trial have not concomitantly been involved in other randomized trials.
• Data regarding any of the subjects in the study has not been previously published unless specified.
• Data will be made available to the editors of the journal for review or query upon request
Data Sharing Statement:
The data will be made available on request.
