The patients' mean age was 37.0 ± 4.2 years, the partners' mean age was 39.0 ± 5.9 years, the mean total motile sperm count pre-insemination was 37.0 ± 44.6 million, basal serum FSH 9.9 ± 9.1 IU/L, serum TSH 1.7 ± 0.8 IU/L, serum AMH 2.5 ± 2.8 ng/ml, AFC 13.1 ± 10.7 and patient weight 75.9 ± 21.0 kg. The causes of infertility were listed in Table 1.

Table 1 Causes of infertility among all subjects:

Among all subjects 49% were stimulated per protocol, 5.6% failed to stimulate, and 45.4% were overstimulated. For the sake of the following data, FD doses are per day.

The results of the stratified outcomes per dose group for ovarian stimulation are presented in Table 2.

Table 2 Ovarian stimulation response among all subjects in general and stratifiedOvarian stimulation response stratified for AFC

AFC was available on 134 subjects. Among subjects with AFC ≥ 10 (N = 78), doses ranged from (2–12 mcg daily), 53% stimulated per protocol, 8% failed to stimulate, and 40% overstimulated. Among AFC ≥ 10 & FD dose ≤ 3mcg daily (range 2–3 mcg), (N = 41): 73% stimulated per protocol, 2.4% failed to stimulate and 24.6% overstimulated. Among women with AFC ≥ 10 & FD dose > 3 mcg daily (range 4.00 to 12 mcg) (N = 37): 29% stimulated per protocol, 11% failed to stimulate, and 60% overstimulated. This comparison did not take into consideration body weight or serum AMH.

For women with an AFC 6–9 (N = 20), 25% were stimulated per the protocol, and 75% were over-stimulated, dose range 3–12 mcg daily. For those with AFC 6–9 and dose 6-12mcg daily (N = 17), 12% were stimulated per the protocol and 88% were over-stimulated, 0% failed to stimulate. For those with AFC 6–9 and stimulated with 3mcg daily (N = 3) 100% stimulated per protocol, 0 were over-stimulated and 0 failed to stimulate. None of these subjects were stimulated with between 3.3 and 5.6 mcg daily. Weight was not taken into consideration for this analysis, nor was serum AMH.

Among women with AFC < 6 (N = 36); daily doses ranged (3-12mcg), 44% stimulated per protocol, 50% over-stimulated, and 6% failed to stimulate. Among women with AFC < 6 and FSH dose ≤ 4mcg (3–4 mcg, range) (N = 6): 0% failed to stimulate, 50% stimulated per the protocol, and 50% over-stimulated. Among women with AFC < 6 and FD dose 4.3 to 12 mcg (N = 30); 47% were over-stimulated and 47% were stimulated per the protocol and 7% failed to stimulate. Among women with AFC < 6 and FSH dose = 3 mcg (N = 3): 100% stimulated per protocol. This analysis did not consider body weight or serum AMH.

Ovarian stimulation response stratified for AMH

AMH levels were available on 113 subjects. Among women with serum AMH ≥ 1.5 ng/ml and FD dose of 2 or 3mcg daily (N = 29), 79% stimulated per protocol, 17% over-stimulated, and 3.4% failed to stimulate. Among women with serum AMH ≥ 1.5 ng/ml and FD dose > 3 mcg daily (range 3.66–12.0 mcg) (N = 29) 62% were over-stimulated, 20% were stimulated per the protocol and 18% failed to stimulate.

Among women with serum AMH ≥ 1.0 ng/ml and < 1.5 ng/dl (N = 19) and FD dose range of 3 to 12 mcg, 53% were stimulated per the protocol and 47% over stimulated. Among women in this group stimulated with 3 to 6 mcg daily (N = 9). 67% stimulated per the protocol and 33% over-stimulated, 0 failed to stimulate. Among women in this group stimulated with 3 to 4 mcg daily 20% were over-stimulated and 80% stimulated per protocol (N = 6). Among women stimulated with 7–12 mcg daily (N = 10) 60% over stimulated and 40% were stimulated per protocol. None of the patients with AMH ≥ 1.0 ng/ml and < 1.5 ng/dl failed to stimulate. None of the subjects were stimulated with a FD dose between 6 and 7 mcg daily. This comparison did not consider body weight.

Among women with serum AMH < 1.0 ng/ml and FD dose ≤ 4mcg (range 3.0–4.0 mcg) (N = 5) 75% were stimulated per the protocol and 25% were over-stimulated, 0% failed to stimulate. Among women with AMH < 1.0 ng/ml and FD dose 6.0 to 12.0 mcg daily (N = 31): 29% were stimulated per protocol, 48% were over-stimulated, and 23% failed to stimulate. None of the subjects received a FD daily dose between 4.3 and 5.6 mcg daily.

Ovarian stimulation response stratified for body weight

Bodyweight measurements were available on 71 subjects. Among women with body weight ≥ 80 kg (n = 26, range 81.0–129.7 kg), dose range (3-12mcg daily) 50% stimulated per protocol, 23% failed to stimulate, and 27% over-stimulated.

Among women with body weight ≥ 80 kg and FSH dose was 4-6mcg daily (N = 20, range 81.6–118.8 kg), 50% were stimulated per protocol, 25% failed to stimulate, and 25% over-stimulated.

Only 6 subjects were stimulated with doses greater than 6 mcg daily with bodyweight ≥ 80 kg (range 81.0–129.7 kg), 33% over-stimulated and 50% stimulated per the protocol, and (N = 1) failed to stimulate.

Among women with body weight < 80 kg (N = 45, range 47.6–77.1), 47% were stimulated per the protocol, and 53% over stimulated with a dose range of FD 2–12 mcg daily. All these patients were stimulated.

Among women with body weight < 80 kg and FD dose 2 to 4 mcg daily (N = 17, range 47.6–77.1), 71% were stimulated per the protocol, and 29% were over-stimulated with a dose range of FD 2–12 mcg daily. All of the patients stimulated follicular growth.

Among women with body weight < 80 kg and FD dose 5.33 to 12.0 mcg daily (no subjects were treated with a dose between 4 and 5.33 mcg daily of FD) (N = 28, range 55.0–76.0 kg) 71% over-stimulated and 29% stimulated per protocol.

Stimulation responses are summarized in Table 2

Based on the data above the following recommendations for COH IUI using FD doses were developed for the first cycles.

1) For women with a bodyweight < 80 kg stimulate initially with daily with 2.0–4.0 mcg FD

2) For women with body weight > 80 kg stimulate initially with daily with 4.0–6.0 mcg FD

3) For women with an AFC ≥ 10 stimulate with 2.0–3.0 mcg daily

4) For women with AFC of 6–9 stimulate with 3.0 mcg daily

5) For women with an AFC < 6 stimulate initially with 3.0–4.0 mcg daily

6) For women with serum AMH < 1.5 ng/ml stimulate with FD 3.0–4.0 mcg daily

A combined representation of our dose recommendations is included in Table 3.

Table 3 The daily dosing algorithm for the first Follitropin Delta controlled ovarian stimulation cycle for intercourse or insemination

We compared women who were stimulated based on these dose recommendations (Table 3) for Antral follicle Counts. Those stimulated with the recommended doses of FD were compared to those stimulated with higher doses for rates of stimulation per protocol vs. over-stimulation. Rates of overstimulation were statistically higher p = 0.0004 if these dose guidelines were not followed.

We also compared outcomes based on AMH and those stimulated based on recommended doses were statistically less likely to overstimulate and more likely to stimulate per guidelines as compared to those stimulated with higher doses (p < 0.0001).

When we compared dosing based on body weight. We found that those who were stimulated per our recommendations provided in Table 3 were less likely to over-stimulate and more likely to stimulate per guidelines as compared to women stimulated with higher doses of FD (p = 0.004).

The pregnancy rate for all comers irrespective of age, ovarian reserve, and diagnosis was 11% per insemination performed. Among the subjects that were stimulated with our recommended doses, multiple pregnancy rates were 7.9%. The data of multiple pregnancy rates in women with over-stimulation is biased by conversions to IVF and cancelations with few completing the inseminations, limiting the possibility for results.