Does FSH Increase the Success of IUI Cycles?
Yes, FSH-based ovarian stimulation significantly increases IUI success rates compared to natural cycles or clomiphene citrate, and should be the standard approach for couples with unexplained infertility and adequate sperm parameters (TMSC >10 million). 1
Primary Recommendation for Ovarian Stimulation
In couples with unexplained infertility and men with a total motile sperm count (TMSC) above 10 million, IUI should be combined with ovarian stimulation to improve live birth rates. 1 This represents moderate-strength evidence from comprehensive international guidelines.
FSH vs. Clomiphene Citrate: The Evidence
The superiority of FSH over clomiphene citrate is well-established, though the magnitude of benefit must be weighed against costs and multiple pregnancy risks:
Gonadotropins (FSH) yield significantly higher pregnancy rates than clomiphene citrate (OR = 1.8,95% CI 1.2–2.7), though clomiphene remains an acceptable alternative when cost is a primary concern. 1
A 2018 randomized controlled trial comparing FSH to clomiphene citrate found ongoing pregnancy rates of 31% with FSH versus 26% with clomiphene citrate, though this difference did not reach statistical significance (RR = 1.16,95% CI: 0.93-1.47). 2 Importantly, both groups had similarly low multiple pregnancy rates (1.4% vs 2.2%) when strict cancellation criteria were applied.
An earlier RCT demonstrated pregnancy rates per cycle of 13% with FSH versus 4% with clomiphene citrate (P = 0.02), with all pregnancies being singleton. 3
Clomiphene citrate or tamoxifen are acceptable alternatives to low-dose gonadotropins for lower multiple pregnancy rates and reduced costs, although at a lower live birth rate than with gonadotropins. 1
Optimal FSH Dosing Protocol
When gonadotropins are used in IUI, regimens with 75 IU or lower should be used because higher doses have similar pregnancy rates but increase multiple pregnancy rates. 1, 4
The evidence supports a conservative approach:
Low-dose FSH (75 IU/day starting dose) is recommended as the standard protocol. 4, 5
A late low-dose technique (75 IU/day from cycle day 7 until the leading follicle reaches >17 mm) has proven efficacious, safe, and economical, with pregnancy rates of 13% per cycle and no cases of ovarian hyperstimulation syndrome. 3
Recent data suggests that FSH dosing based on age and ovarian reserve markers (using nomograms) may optimize outcomes and cost-effectiveness, though this approach requires validation in clinical practice. 6
Critical Safety Parameters
To prevent high rates of multiple gestation pregnancies in IUI with ovarian stimulation, IUI should be withheld when more than two dominant follicles >15 mm or more than five follicles >10 mm at the time of hCG injection or LH surge are present. 1, 4, 5
This strict cancellation criterion is essential because:
Multiple pregnancy risk is 10-20% with gonadotropin stimulation without proper cycle management. 5
The goal is to achieve exactly 2 mature follicles (>15mm) to balance success against multiple pregnancy risk. 4
Compared to one dominant follicle, pregnancy rates increase by 5%, 8%, and 8% with two, three, or four dominant follicles, respectively, but multiple pregnancy risk increases to 6%, 14%, and 10% respectively. 1
Cost-Effectiveness Considerations
In couples with unexplained infertility and men with a TMSC of >10 million and a prognosis of pregnancy without assistance <30% within a year, at least three cycles of IUI with ovarian stimulation is the most cost-effective option. 1
The economic analysis demonstrates:
IUI with ovarian stimulation is more cost-effective than proceeding directly to IVF, particularly when strict cancellation criteria minimize multiple pregnancies. 1
At least 3 consecutive IUI cycles should be performed before transitioning to IVF/ICSI, as cycle fecundity remains acceptable through cycle 3. 4, 5
When IVF with elective single embryo transfer achieves ongoing pregnancy rates exceeding 38%, it becomes preferable to IUI with ovarian stimulation. 1
Common Pitfalls to Avoid
Do not add GnRH agonists to gonadotropins as they increase multiple pregnancy rates and costs without improving pregnancy rates. 1, 5
Do not use FSH doses higher than 75 IU/day as a starting dose, as higher doses yield similar pregnancy rates but significantly increase multiple pregnancy risk. 1
Do not proceed with insemination when >2 follicles >15mm develop, as this dramatically increases high-order multiple pregnancy risk without proportional benefit. 4, 5
In women with polycystic ovary syndrome and high AMH levels, standard nomogram-based FSH dosing may not be adequate and requires clinical adjustment. 6
Special Populations
For younger women (<35 years) with elevated basal FSH levels (≥10 U/L), gonadotropin-stimulated IUI remains a viable option with comparable pregnancy outcomes to those with normal FSH, though they require longer stimulation periods and face higher cycle cancellation rates. 7