Dysregulation of FSH in Obesity: Functional and Statistical Analysis

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT02478775
• Collaborator: (none)
• Enrollment: 99
• Location: 1
• Arms: 2
• Actual Duration (Months): 72
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

Excess maternal weight, especially obesity, influences almost every aspect of fertility, from conception to problems during pregnancy. The investigators will use novel statistical methods to clarify the hormonal changes behind reproductive health conditions. A better understanding of reproductive hormonal changes in obese women may offer a way to identify new treatments.

Condition or Disease	Intervention/Treatment	Phase
Obesity; Fertility	Drug: Degarelix (GnRH antagonist); Drug: recombinant FSH; Drug: Cetrorelix	N/A

Detailed Description

Hypothesis. Insufficient FSH (Follicle-stimulating hormone) pulsatility, as seen in obesity, results in inadequate folliculogenesis and reduced ovarian steroid and protein production.

AIM: To test the hypothesis that insufficient FSH pulsatility, as seen in obesity, results in inadequate folliculogenesis and reduced ovarian steroid and protein production. The investigators will determine if exogenous FSH administered in a pulsatile fashion results in a significant increase of ovarian hormones in obese women. Serial inhibin B and E2 levels will be measured in obese and normal weight women undergoing frequent blood sampling studies before and after GnRH (Gonadotropin-releasing hormone) antagonist blockade.

Study Design

• Study Type: Interventional
• Actual Enrollment: 99 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Dysregulation of Follicle Stimulating Hormone (FSH) in Obesity: Functional and Statistical Analysis
• Actual Study Start Date: Jul 1, 2015
• Actual Primary Completion Date: Jun 30, 2021
• Actual Study Completion Date: Jun 30, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Frequent Blood Sampling, Degarelix Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Degarelix (GnRH antagonist) blockade over a 2-day period. This arm was terminated due to Adverse Events and the study was continued with the Cetrorelix product.	Drug: Degarelix (GnRH antagonist); Day-1: Blood samples will be obtained every 10 minutes for 10 hours. After 10 hours of blood samples have been collected, the GnRH antagonist degarelix will be given subcutaneously.; Other Names: Firmagon ; Drug: recombinant FSH; Day-2: Blood samples will again be obtained every 10 minutes for 10 hours. Repeated boluses of exogenous recombinant FSH (rFSH) will be given by IV during this 10 hour visit.; Other Names: rFHS
Experimental: Frequent Blood Sampling, Cetrorelix Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period.	Drug: recombinant FSH; Day-2: Blood samples will again be obtained every 10 minutes for 10 hours. Repeated boluses of exogenous recombinant FSH (rFSH) will be given by IV during this 10 hour visit.; Other Names: rFHS ; Drug: Cetrorelix; Day-1: Blood samples will be obtained every 10 minutes for 10 hours. After 10 hours of blood samples have been collected, the GnRH antagonist Cetrorelix will be given subcutaneously.; Other Names: Cetrotide

Outcome Measures

Primary Outcome Measures

1. Difference Between Peak Inhibin B [Every 10 minutes over 2 10-hour frequent blood sampling sessions.]

   This is defined as the maximum hormone value during Day 1 of the study subtracted from the maximum hormone value during Day 2.

Secondary Outcome Measures

1. Peak Inhibin B Per Subject [Every 10 minutes over 10 hours on Day 1 and Day 2 of the study.]

   Peak inhibin B will be measured every 10 minutes during day 1 and day 2 of the study. The highest inhibin B value will be defined as the peak.

2. Peak E2 Per Subject [Every 10 minutes over 10 hours of Day 1 and Day 2 of the study.]

   E2 will be measured every 10 minutes on Day 1 and Day 2 of the study. The highest E2 value will be designated as the peak E2 value.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 39 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Age between 21 to 39 years old with regular menstrual cycles every 25-40 days

• Body mass of 18.5 kg/m2-24.9kg/m2 (normal weight controls) or greater than 30.0 kg/m2 (obese group)

• Prolactin and thyroid-stimulating hormone (TSH) within normal laboratory ranges at screening

• Baseline hemoglobin >11 gm/dl.

Exclusion Criteria:

• Diagnosis of polycystic ovary syndrome (PCOS), defined by the 2003 Rotterdam criteria as suggested by 2012 NIH Workshop

• History of chronic disease affecting hormone production, metabolism or clearance or use of thiazolidinediones or metformin (known to interact with reproductive hormones)

• Use of hormones affecting hypothalamic-pituitary-gonadal (HPO) axis (such as hormonal contraceptives) within 3 months of entry

• Strenuous exercise (>4 hours of intense physical activity per week)

• Pregnancy

• Breast-feeding

• Current attempts to conceive

• Significant recent weight loss or gain

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Clinical and Translational Research Center	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver

Investigators

• Principal Investigator: Alex Polotsky, MD, University of Colorado, Denver

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 6, 2020
• Informed Consent Form - Jan 8, 2021

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT02478775
• Other Study ID Numbers: 15-0474; UL1TR001082
• First Posted: Jun 23, 2015
• Last Update Posted: Apr 7, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of Colorado, Denver: obesity; fertility; infertility; reproductive hormones
• Additional relevant MeSH terms: Obesity; Cetrorelix

Study Results

Participant Flow

Pre-assignment Detail	Some participants were excluded after signing the consent.

Arm/Group Title	Experimental: Frequent Blood Sampling, Degarelix	Experimental: Frequent Blood Sampling, Cetrorelix: Normal Weight	Experimental: Frequent Blood Sampling, Cetrorelix: Obese
Arm/Group Description	Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Degarelix (GnRH antagonist) blockade over a 2-day period. This arm was terminated due to Adverse Events and the study was continued with the Cetrorelix product.	Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period. Normal weight participants = 18.5 to 24.9 BMI	Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period. Obese participants = BMI of >30
Period Title: Overall Study
STARTED	6	27	27
COMPLETED	6	27	27
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Experimental: Frequent Blood Sampling, Degarelix	Experimental: Frequent Blood Sampling, Cetrorelix: Normal Weight	Experimental: Frequent Blood Sampling, Cetrorelix: Obese	Total
Arm/Group Description	Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Degarelix (GnRH antagonist) blockade over a 2-day period. This arm was terminated due to Adverse Events and the study was continued with the Cetrorelix product. BMI = 18.5 to 24.9 BMI	Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period. Normal weight participants = 18.5 to 24.9 BMI	Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period. Obese participants = BMI of >30	Total of all reporting groups
Overall Participants	6	27	27	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.5 (5.9)	27.2 (4.7)	31.9 (4.1)	29.6 (5)
Sex: Female, Male (Count of Participants)
Female	6 100%	27 100%	27 100%	60 100%
Male	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	3 11.1%	3 11.1%	6 10%
Not Hispanic or Latino	6 100%	24 88.9%	24 88.9%	54 90%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	1 3.7%	1 1.7%
Asian	1 16.7%	1 3.7%	0 0%	2 3.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	1 3.7%	6 22.2%	7 11.7%
White	5 83.3%	24 88.9%	20 74.1%	49 81.7%
More than one race	0 0%	1 3.7%	0 0%	1 1.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	6 100%	27 100%	27 100%	60 100%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	22.5 (2.5)	22.4 (1.5)	37.7 (6.2)	30.1 (8.9)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	59.8 (4.2)	61.1 (5.4)	102 (19.3)	81.6 (24.9)

Outcome Measures

1. Primary Outcome

Title	Difference Between Peak Inhibin B
Description	This is defined as the maximum hormone value during Day 1 of the study subtracted from the maximum hormone value during Day 2.
Time Frame	Every 10 minutes over 2 10-hour frequent blood sampling sessions.

Outcome Measure Data

Analysis Population Description

The Degarelix arm is excluded because no data was collected from those participants. The Degarelix arm was terminated due to adverse events and was replaced with the Cetrorelix arm.

Arm/Group Title	Experimental: Frequent Blood Sampling, Cetrorelix: Normal Weight	Experimental: Frequent Blood Sampling, Cetrorelix: Obese
Arm/Group Description	Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period. Normal weight participants = 18.5 to 24.9 BMI	Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period. Obese participants = BMI of >30
Measure Participants	27	27
Mean (Standard Deviation) [picograms/mL]	100.8 (73.7)	38.8 (37.9)

2. Secondary Outcome

Title	Peak Inhibin B Per Subject
Description	Peak inhibin B will be measured every 10 minutes during day 1 and day 2 of the study. The highest inhibin B value will be defined as the peak.
Time Frame	Every 10 minutes over 10 hours on Day 1 and Day 2 of the study.

Outcome Measure Data

Analysis Population Description

The Degarelix arm is excluded because no data was collected from those participants. The Degarelix arm was terminated due to adverse events and was replaced with the Cetrorelix arm.

Arm/Group Title	Experimental: Frequent Blood Sampling, Cetrorelix: Normal Weight	Experimental: Frequent Blood Sampling, Cetrorelix: Obese
Arm/Group Description	Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period. Normal weight participants = 18.5 to 24.9 BMI	Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period. Obese participants = BMI of >30
Measure Participants	27	27
Day 1 maximum	103.5 (43.8)	87.5 (45.3)
Day 2 maximum	226.5 (105.3)	126.3 (52.5)

3. Secondary Outcome

Title	Peak E2 Per Subject
Description	E2 will be measured every 10 minutes on Day 1 and Day 2 of the study. The highest E2 value will be designated as the peak E2 value.
Time Frame	Every 10 minutes over 10 hours of Day 1 and Day 2 of the study.

Outcome Measure Data

Analysis Population Description

The Degarelix arm is excluded because no data was collected from those participants. The Degarelix arm was terminated due to adverse events and was replaced with the Cetrorelix arm.

Arm/Group Title	Experimental: Frequent Blood Sampling, Cetrorelix: Normal Weight	Experimental: Frequent Blood Sampling, Cetrorelix: Obese
Arm/Group Description	Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period. Normal weight participants = 18.5 to 24.9 BMI	Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period. Obese participants = BMI of >30
Measure Participants	27	27
Day 1	65.1 (58.0)	72.5 (37.7)
Day 2	137.7 (61.8)	99.1 (41.6)

Adverse Events

Time Frame	7 Days
Arm/Group Title	Experimental: Frequent Blood Sampling, Degarelix		Experimental: Frequent Blood Sampling, Cetrorelix: Normal Weight		Experimental: Frequent Blood Sampling, Cetrorelix: Obese
Arm/Group Description	Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Degarelix (GnRH antagonist) blockade over a 2-day period. This arm was terminated due to Adverse Events and the study was continued with the Cetrorelix product. BMI = 18.5 to 24.9 BMI		Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period. Normal weight participants = 18.5 to 24.9 BMI		Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period. Obese participants = BMI of >30
All Cause Mortality
	Experimental: Frequent Blood Sampling, Degarelix		Experimental: Frequent Blood Sampling, Cetrorelix: Normal Weight		Experimental: Frequent Blood Sampling, Cetrorelix: Obese
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/27 (0%)		0/27 (0%)
Serious Adverse Events
	Experimental: Frequent Blood Sampling, Degarelix		Experimental: Frequent Blood Sampling, Cetrorelix: Normal Weight		Experimental: Frequent Blood Sampling, Cetrorelix: Obese
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/27 (0%)		0/27 (0%)
Other (Not Including Serious) Adverse Events
	Experimental: Frequent Blood Sampling, Degarelix		Experimental: Frequent Blood Sampling, Cetrorelix: Normal Weight		Experimental: Frequent Blood Sampling, Cetrorelix: Obese
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		0/27 (0%)		0/27 (0%)
Reproductive system and breast disorders
Delay of menses	5/6 (83.3%)	5	0/27 (0%)	0	0/27 (0%)	0
Hot flashes	2/6 (33.3%)	2	0/27 (0%)	0	0/27 (0%)	0

Limitations/Caveats

The Degarelix arm is excluded from outcome measure data because no usable data could be collected from those participants. The Degarelix arm was terminated due to adverse events and was replaced with the Cetrorelix arm.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.