Pulsatile FSH for Obesity-Related Infertility

Recruiting at 1 trial location

Overseen By Asma Giornazi, MS

Age: 18 - 65

Sex: Female

Trial Phase: Phase 1

Sponsor: University of Colorado, Denver

Disqualifiers: PCOS, Thyroid disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

5 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Pulsatile Intravenous FSH for obesity-related infertility?

Research shows that recombinant follicle-stimulating hormone (rFSH) can help overcome dysfunctional ovarian function in women with obesity, which is a common cause of infertility. Additionally, rFSH has been a mainstay in treating ovulatory dysfunction, demonstrating higher purity and effectiveness in stimulating ovulation. ^{1 2 3 4 5}

Is Pulsatile FSH safe for use in humans?

Studies on recombinant FSH (Puregon) show it is generally well-tolerated in humans, with mild and short-lived local reactions. No significant safety differences were found when compared to urinary FSH in women undergoing fertility treatments. ^{2 6 7 8 9}

How is Pulsatile Intravenous FSH different from other treatments for obesity-related infertility?

Pulsatile Intravenous FSH is unique because it delivers follicle-stimulating hormone (FSH) in a pulsatile manner, which mimics the body's natural hormone release patterns, potentially improving ovulation in women with obesity-related infertility. This method contrasts with other treatments that may use continuous or less frequent dosing. ^{2 8 10 11 12}

What is the purpose of this trial?

Hypothesis: The investigators hypothesize that pulsatile FSH intravenous administration to women with obesity will correct the Reprometabolic Syndrome (RMS) luteal deficiency phenotype. Specific Aim: To test the hypothesis that pulsatile IV administration of FSH will rescue the impaired folliculogenesis and relative hypogonadotropic hypogonadism, characteristic of obesity. The investigators will accomplish this by administering a cycle of pulsatile FSH to women with obesity and comparing their hormone output to a cycle using conventional, daily FSH injection at the identical daily dose. The primary outcome will be luteal phase progesterone excretion.

Research Team

Nanette Santoro, MD

Principal Investigator

University of Colorado School of Medicine

Eligibility Criteria

This trial is for women with obesity who are experiencing infertility, specifically due to Reprometabolic Syndrome (RMS) luteal deficiency. Participants should have a history of impaired folliculogenesis and relative hypogonadotropic hypogonadism associated with obesity.

Inclusion Criteria

Serum total and free testosterone within the 95% CI for women with obesity previously studied in our laboratory

Acceptance of the indwelling catheter and willingness to take part in the study

My BMI is between 30 and 40.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment - Pulsatile IV FSH Dosing

Participants receive pulsatile IV FSH via a portable infusion pump every 90 minutes for 7-12 days

1-2 weeks

Daily monitoring (in-person or virtual)

Washout Period

A 1-month washout period to avoid carryover effects between treatment cycles

4 weeks

Treatment - Conventional Subcutaneous FSH Dosing

Participants receive daily subcutaneous injections of FSH for 7-12 days

1-2 weeks

Daily monitoring (in-person or virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Pulsatile Intravenous FSH

Trial Overview The study aims to see if giving Follicle Stimulating Hormone (FSH) in pulses through an IV can correct RMS luteal deficiency in obese women. It compares this method to the standard daily FSH injections by measuring hormone levels during the luteal phase.

Participant Groups

Group I: Pulsatile IV FSH Dosing Experimental Treatment 1 Intervention

participants will receive the same daily rhFSH dose (based on clinical practice criteria); however, it will be delivered via a portable infusion pump with reservoir (Avocet Infusion Pump, Eitan Medical LTD) that will provide an IV bolus (100-500 µl) every 90 minutes, a frequency that has previously been shown to result in physiologic ovulatory cycles in GnRH deficient women (Martin). The total gonadotropin dose delivered over a 24 hour period will be typically 75-450 IU, assigned based on standard of care clinical criteria (max dose is 900IU per clinical care guidelines). Participants will be provided with a 100mL preloaded reservoir, calibrated to deliver the approved standard of care dosing, in 16 boluses (100-500µl) over 24 hours (q 90min), for 7-12 days. Each 100 ml reservoir has capacity for 200 doses if the volume is 500 µl, which is sufficient for the typical 7- 12-day protocol.

Group II: Conventional Subcutaneous FSH Dosing Active Control 1 Intervention

A daily gonadotropin dose (typically 75-450 IU) will be assigned and adjusted, based on clinical criteria and, if known, past response to hormones. Recombinant human FSH (rhFSH) will be given as a daily subcutaneous injection, as is performed, by patients at home, in routine clinical practice.

Pulsatile Intravenous FSH is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Gonal-F for:

• Infertility
• Anovulation
• Assisted reproductive technology

Approved in United States as Gonal-F for:

• Infertility
• Anovulation
• Assisted reproductive technology

Approved in Canada as Puregon for:

• Infertility
• Anovulation
• Assisted reproductive technology

Approved in Japan as Follistatin for:

• Infertility
• Anovulation
• Assisted reproductive technology

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Findings from Research

A study involving 54 women (27 normal-weight and 27 with obesity) demonstrated that intravenous pulsatile administration of recombinant follicle-stimulating hormone (rFSH) can normalize hormone levels in women with obesity, despite their underlying ovarian dysfunction.

While pulsatile rFSH treatment improved estradiol and inhibin B levels in women with obesity to match those of normal-weight women, it highlighted that obesity is associated with reduced ovarian function, indicating a need for targeted fertility treatments in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of pulsatile intravenous follicle-stimulating hormone treatment on ovarian function in women with obesity. Luu, TH., Kuhn, K., Bradford, AP., et al.[2023]

A study involving 27 cycles of ovulation induction in women with polycystic ovarian syndrome showed that administering lower doses of recombinant follicle stimulating hormone (FSH) on alternate days resulted in ovulation in 22 out of 27 cycles.

The treatment led to six pregnancies, with four pregnancies proceeding to term, indicating that low-dose FSH therapy can be an effective and safer option for patients resistant to previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ovulation induction with low dose alternate day recombinant follicle stimulating hormone (Puregon). Buckler, HM., Robertson, WR., Anderson, A., et al.[2019]

In a cohort analysis involving couples undergoing IVF/ICSI across 158 clinics in 15 Latin American countries, adding either urinary or recombinant LH to the standard rFSH treatment did not improve the number of mature oocytes recovered or the delivery rates per initiated cycle.

The study concluded that the type of controlled ovarian stimulation, whether using FSH alone or in combination with LH, has minimal impact on the outcomes of assisted reproductive technology, suggesting that simpler and more accessible treatment options could be preferred.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of neither recombinant nor urinary luteinizing hormone was associated with an improvement in the outcome of autologous in vitro fertilization/intracytoplasmatic sperm injection cycles under regular clinical settings: a multicenter observational analysis. Schwarze, JE., Crosby, JA., Zegers-Hochschild, F.[2022]

Recombinant human FSH (rhFSH) offers a purer and more effective treatment option for women with ovulatory dysfunction compared to traditional urinary-derived FSH, addressing issues like contamination and variable composition.

rhFSH not only improves the treatment of infertility but also enables the development of new FSH products with varied pharmacokinetic and pharmacodynamic properties, potentially expanding treatment options for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of follicle-stimulating hormone for the treatment of female infertility - current concepts. Pang, SC.[2016]

In a study involving 20 participants (10 women and 10 men), the combination of lipid/heparin and insulin infusion significantly reduced levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) compared to saline control, indicating a potential mechanism for hypogonadotropic hypogonadism in obesity.

The results suggest that elevated fatty acids and insulin together can acutely suppress gonadotropin secretion, highlighting the importance of the metabolic environment in regulating hormone levels in the hypothalamic-pituitary-gonadal axis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute recapitulation of the hyperinsulinemia and hyperlipidemia characteristic of metabolic syndrome suppresses gonadotropins. Chosich, J., Bradford, AP., Allshouse, AA., et al.[2021]

A study involving 22 healthy female volunteers found that two formulations of recombinant human follicle stimulating hormone (recFSH) had similar bioavailability after correcting for injection losses, indicating they can be used interchangeably.

Both the syringe and Puregon(R)Pen methods were well tolerated, with only mild and short-lived local reactions reported, suggesting a good safety profile for both administration techniques.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence of subcutaneous injections of recombinant human follicle stimulating hormone (Puregon(R)) by Pen-injector and syringe. Voortman, G., van de Post, J., Schoemaker, RC., et al.[2019]

In a study involving 99 infertile women undergoing IVF, the recombinant FSH preparation Org 32489 (Puregon) showed similar efficacy to urinary FSH (Metrodin) in terms of the total number of oocytes recovered, with 9.7 oocytes for Org 32489 compared to 8.9 for urinary FSH.

While Org 32489 demonstrated higher ongoing pregnancy rates per attempt (30.2%) and per transfer (34.0%) compared to urinary FSH (17.4% and 18.8%, respectively), these differences were not statistically significant, and both treatments showed comparable safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of recombinant follicle stimulating hormone (Puregon) in infertile women pituitary-suppressed with triptorelin undergoing in-vitro fertilization: a prospective, randomized, assessor-blind, multicentre trial. Hedon, B., Out, HJ., Hugues, JN., et al.[2019]

In a clinical trial involving 172 women with infertility, recombinant FSH (Puregon) demonstrated a higher efficiency in inducing ovulation compared to urinary FSH (Metrodin), with similar cumulative ovulation rates of 95% and 96%, respectively.

The recombinant FSH group required a significantly lower total dose (750 IU vs. 1,035 IU) and shorter treatment period (10 days vs. 13 days) to achieve ovulation, indicating its superior efficacy in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant follicle-stimulating hormone (FSH; Puregon) is more efficient than urinary FSH (Metrodin) in women with clomiphene citrate-resistant, normogonadotropic, chronic anovulation: a prospective, multicenter, assessor-blind, randomized, clinical trial. European Puregon Collaborative Anovulation Study Group. Coelingh Bennink, HJ., Fauser, BC., Out, HJ.[2019]

Recombinant follicle stimulating hormone (rFSH) has undergone extensive clinical trials in assisted reproduction, showing that it effectively stimulates ovarian function even without luteinizing hormone (LH).

In a study involving around 1000 patient cycles, rFSH treatment resulted in significantly more oocyte retrieval, embryo production, and ultimately more pregnancies compared to urinary FSH, highlighting its efficacy in IVF procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant follicle stimulating hormone (rFSH; Puregon) in assisted reproduction: more oocytes, more pregnancies. Results from five comparative studies. Out, HJ., Mannaerts, BM., Driessen, SG., et al.[2019]

In a study of 21 anovulatory infertile patients treated with pulsatile gonadotropin-releasing hormone (GnRH), 10 patients ovulated and 8 of them conceived, resulting in a total of 10 pregnancies, indicating the efficacy of this treatment for inducing ovulation.

The treatment was most successful in patients with a body mass index (BMI) of less than 21 and a normal LH/FSH ratio, while those with elevated BMI or LH levels generally did not respond well, suggesting specific patient characteristics are important for treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of ovulation with subcutaneous pulsatile gonadotropin-releasing hormone: correlation with body weight and other parameters. Thomas, AK., Mander, J., Hale, J., et al.[2019]

In a study of 10 severely overweight infertility patients, a 6-week very low calorie diet led to a significant 45% decrease in nocturnal urinary LH levels, indicating that weight reduction may lower LH secretion, which could favor folliculogenesis.

The decrease in LH was inversely related to insulin sensitivity, suggesting that improvements in glucose metabolism and insulin levels after weight loss may play a more crucial role in regulating LH than just the reduction in body fat.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The decrease in luteinizing hormone secretion in response to weight reduction is inversely related to the severity of insulin resistance in overweight women. Bützow, TL., Lehtovirta, M., Siegberg, R., et al.[2011]

In a study involving 44 infertile women undergoing IVF-ET, both follitropin-alpha and follitropin-beta showed similar efficacy in terms of ovarian response and pregnancy outcomes, indicating that either preparation can be effectively used for superovulation.

However, follitropin-beta was associated with a higher incidence and severity of local injection site reactions compared to follitropin-alpha, suggesting that while both are effective, follitropin-alpha may be better tolerated in terms of injection site discomfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of the efficacy and tolerability of two recombinant human follicle-stimulating hormone preparations in patients undergoing in vitro fertilization-embryo transfer. Brinsden, P., Akagbosu, F., Gibbons, LM., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Effects of pulsatile intravenous follicle-stimulating hormone treatment on ovarian function in women with obesity. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Ovulation induction with low dose alternate day recombinant follicle stimulating hormone (Puregon). [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Addition of neither recombinant nor urinary luteinizing hormone was associated with an improvement in the outcome of autologous in vitro fertilization/intracytoplasmatic sperm injection cycles under regular clinical settings: a multicenter observational analysis. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Use of follicle-stimulating hormone for the treatment of female infertility - current concepts. [2016]

5. United States pubmed.ncbi.nlm.nih.gov

Acute recapitulation of the hyperinsulinemia and hyperlipidemia characteristic of metabolic syndrome suppresses gonadotropins. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Bioequivalence of subcutaneous injections of recombinant human follicle stimulating hormone (Puregon(R)) by Pen-injector and syringe. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of recombinant follicle stimulating hormone (Puregon) in infertile women pituitary-suppressed with triptorelin undergoing in-vitro fertilization: a prospective, randomized, assessor-blind, multicentre trial. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Recombinant follicle-stimulating hormone (FSH; Puregon) is more efficient than urinary FSH (Metrodin) in women with clomiphene citrate-resistant, normogonadotropic, chronic anovulation: a prospective, multicenter, assessor-blind, randomized, clinical trial. European Puregon Collaborative Anovulation Study Group. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Recombinant follicle stimulating hormone (rFSH; Puregon) in assisted reproduction: more oocytes, more pregnancies. Results from five comparative studies. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Induction of ovulation with subcutaneous pulsatile gonadotropin-releasing hormone: correlation with body weight and other parameters. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

The decrease in luteinizing hormone secretion in response to weight reduction is inversely related to the severity of insulin resistance in overweight women. [2011]

12. United States pubmed.ncbi.nlm.nih.gov

A comparison of the efficacy and tolerability of two recombinant human follicle-stimulating hormone preparations in patients undergoing in vitro fertilization-embryo transfer. [2019]