This trial tested a novel method for giving rFSH to improve ovarian function in obese women without PCOS who are struggling to conceive.

Study Background

WHAT

• Prospective comparator study

• Investigated effects of pulsatile IV recombinant follicle stimulating hormone (rFSH) in women of normal vs. obese weight after using an antagonist of gonadotropin-releasing hormone (GnRH) to suppress endogenous gonadotropins FSH and luteinizing hormone (LH)

WHY

• Unclear role of FSH in ovarian function in non-PCOS obesity

• Subcutaneous (subQ) FSH has variable absorption and requires BMI-based dosing

• Able to use GnRH antagonist to suppress body’s natural secretion of FSH to understand impact of exogenous IV FSH

WHEN/WHERE

• January 2016-June 2021, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

WHO

Inclusion Criteria:

• Trying to conceive and living in Denver Metro

• Ages 21-39 years, normal or high BMI (18.5–24.9 kg/m2 or ≥30 kg/m2); regular menstrual cycles

• Normal prolactin, thyroid stimulating hormone, complete metabolic panel and blood count

• Strenuous exercise limited to < 4 hours per week

Exclusion Criteria:

• Breast feeding

• Recent weight gain (>2 lbs/weekly) in past three months

• Polycystic ovary syndrome (PCOS) or another chronic disease affecting hormone production, metabolism, or clearance

• Use of thiazolidinediones, metformin, or hormone-containing meds/ supplements in past 90 days

HOW

• 26 hour study commenced at beginning of menstrual cycle (Day 2-7)

  • 1:30pm: received in-dwelling IV catheter and pregnancy test

  • 2pm: drew 3-4 mL blood every ten minutes for ten hours, measuring LH, FSH, Inhibin B, and estradiol (E2)

  • 12 am: injected GNRH antagonist Cetrotide (cetrorelix) 3 mg subQ—> sleep

  • 6 am: Cetrotide “booster” 0.25 mg + IV rFSH 30iu given hourly x 10 hours + resumption of q10min blood draws x 10 hours

Statistics

• Determined a priori needed sample size for 80% power (n = 54) with alpha 0.05

• Between group differences and/or study days: two-sample paired t-tests for continuous variables, Fisher’s exact tests for categorical variables

• Linear regression was used to adjust BMI group differences for age, cycle day and AMH

Results

• Women of normal BMI were younger (age 27 vs. 32, p<0.001) and had lower average TSH levels (but all euthyroid); both groups comparable cycle lengths, waist: hip ratios, prolactin levels, and AMH levels

• LH levels consistently lower in high vs. normal BMI group on Day 1, Cetrotide comparably suppressed levels in both groups on Day 2

• FSH levels similar on Day 1, still similar on Day 2 post-FSH: similar AUC, Vd, urinary concentrations, and serum FSH clearance

• Cetrotide

  • similar pharmacokinetic profiles between groups

  • max concentrations 1hr post-booster dose, then slow decline

• Inhibin B and estradiol (E2)

  • E2 and inhibin B levels at baseline higher in normal BMI group

  • In both groups IV FSH induced increases in maximum E2 and inhibin B levels between baseline and Day 2 stimulation, but high BMI group had less response (high BMI increases achieved levels comparable to those observed at baseline in normal BMI)

  • High BMI group vs. normal had significantly reduced FSH effects vs. normal group

  • Per unit INcrease in BMI observed 1.61 pg/mL and 2.82 pg/mL DEcrease in max responses to E2 and inhibin B respectively

Authors’ Thoughts

• Giving IV pulses of FSH in the short term partially compensates, but does not completely correct, for the relative hypogonadism seen in obesity

• Cetrotide 3mg + booster successfully suppressed LH suppression

• Diurnal variation in hormones and age differences could have contributed to observed between-group differences

• Future studies should look at rFSH for longer durations and correlate with AMH, AFC, and age

This Pharmacist’s Thoughts

• (+) active comparator arm in prospective trial

• (-) lack of explanation about adverse events, especially in light of Degarelix arm discontinuation due to adverse events

• (-) study replicability lowered due to lack of transparency on rFSH manufacturer - locally compounded vs. FDA approved? (Disclosed manufacturers sources of cetrorelix and dagarelix but not rFSH)

  Conclusions

This study demonstrated the potential to further explore the role of rFSH in improving ovarian function in obese women trying to conceive.

Resources

Borgert BJ, Bacchus MW, Hernandez AD, Potts SN, Campbell KJ. The availability of gonadotropin therapy from FDA-approved pharmacies for men with hypogonadism and infertility. Sex Med. 2023;11(2):qfad004. Published 2023 Apr 10. doi:10.1093/sexmed/qfad004

Kumar TR. Rerouting of follicle-stimulating hormone secretion and gonadal function. Fertil Steril. 2023;119(2):180-183. doi:10.1016/j.fertnstert.2022.12.005

Luu TH, Kuhn K, Bradford AP, Wempe MF, Wittenburg L, Johnson RL, Carlson NE, Kumar TR, Polotsky AJ, Effects of Pulsatile IV FSH Treatment on Ovarian Function in Women with Obesity, Fertility and Sterility (2023), doi: https://doi.org/10.1016/j.fertnstert.2023.05.170

University of Colorado, Denver. Dysregulation of FSH in Obesity: Functional and Statistical Analysis. ClinicalTrials.gov identifier: NCT02478775. Updated April 7, 2022. Accessed June 12, 2023. https://clinicaltrials.gov/ct2/show/NCT02478775