Effects of Oral vs. Non-oral Contraceptives on the GH/IGF-1 Axis

• Sponsor: Penn State University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02367833
• Collaborator: Massachusetts General Hospital (Other), Purdue University (Other)
• Enrollment: 60
• Location: 1
• Arms: 4
• Duration (Months): 47
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

This study will determine whether the negative effects of combined oral contraceptive (COC) therapy on the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and bone turnover are dependent on the route of administration such that an attenuation of these effects is observed when a comparable dose of non-oral transdermal contraceptive (TDC) and contraceptive vaginal ring therapy (CVR) are also tested.

Condition or Disease	Intervention/Treatment	Phase
Bone; Disorder, Development and Growth	Drug: Combined Oral Contraceptive; Drug: Transdermal Contraceptive; Drug: Contraceptive Vaginal Ring	Phase 4

Detailed Description

This study is a preclinical, multi-site trial (Penn State University and Purdue University) that will determine whether the negative effects of combined oral contraceptive (COC) therapy on bone turnover are dependent on the route of administration such that an attenuation of these effects is observed when a comparable dose of non-oral transdermal contraceptive (TDC) therapy and contraceptive vaginal ring (CVR) therapy are also tested. Millions of women use COC therapy for birth control purposes or regulation of menstrual cycles. TDC and CVR therapies are relatively new FDA-approved contraceptive alternatives to COC. The purpose of the proposed project is to address the potential mechanism(s) by which oral ethinyl estradiol (EE) may negatively impair bone via "first pass" effects on the liver and compare these effects to transdermally-administered and vaginally-administered EE in young women. We will assess mechanistic effects by way of 2-day serial sampling and by an insulin-like growth factor (IGF-1) generation test. The IGF-1 generation test was developed over 20 years ago and is currently used to diagnose growth hormone (GH) insensitivity. IGF-1 generation tests may also be used to amplify effects not observable by the assessment of fasting or serial concentrations of systemic IGF-1(secreted by the liver) and its associated binding proteins. This study will be the first study to examine the physiological mechanisms whereby the route of estrogen administration affects the GH/IGF-1 axis and bone turnover in young women.

The overall purpose of this study is to explore differences in liver metabolism and bone turnover of oral versus transdermal and vaginal contraceptive therapy. In an effort to expose the route-dependent effects of oral versus transdermal and vaginal contraceptive therapy on liver and bone metabolism, we will examine the effects of ethinyl estradiol on serially-assessed fasting concentrations of the GH/IGF-1 axis and bone turnover and explore physiological mechanisms underlying hepatic responsiveness to oral versus transdermal and vaginal contraceptive therapy using an IGF-1 Generation Test as a probe.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Primary Mechanisms Underlying the Effects of Oral vs. Non-oral Contraceptives on the GH/IGF-1 Axis and Bone Metabolism in Young Women
• Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Dec 1, 2017
• Actual Study Completion Date: Dec 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Combined Oral Contraceptives (COC) Apri (or generic equivalent - Reclipsen) (30µg/d EE, 150 µg/d desogestrel) is a monophasic dosing regimen of 21 active and 7 placebo pills. On Day 1 of the Intervention, participants in the COC group will begin taking the COC pill. Each participant in this group will ingest active pills from the first pack each day for the first 21 days. Pills ingested on days 22 through 28 are placebo pills. A second pill pack will begin on day 29 and pills with active ingredients will be ingested from the second pack each day for days 29-49. On day 50, the participants will immediately begin a 3rd pill pack, if the post-study testing is still occurring, and will ingest a pill with active ingredients from the third pack for days 50-56 (or for as long as the post-study testing is occurring).	Drug: Combined Oral Contraceptive; The proposed study is a preclinical, multi-site trial comparing the short-term effects of oral and non-oral ethinyl estradiol on the GH/IGF-1 axis and bone metabolism. Using a prospective repeated measures design, we will test the effects of 2 cycles of combined oral contraceptive (Apri or Reclipsen) on the GH/IGF-1 axis.; Other Names: Apri (Reclipsen)
Experimental: Transdermal Contraceptive (TDC) Participants in the TDC group will apply a 20 cm2 patch (Xulane: 20µg/d EE,150µg/d norelgestromin) to the abdomen, upper arm or buttock. The patch will be changed once weekly on the same day each week for weeks 1-3 (days 1-21, removed on day 22) and weeks 5-8 (days 29-56). Week 4 (days 22-28) will be a patch-free week. As soon as the post-study testing is complete, subjects will remove the patch.	Drug: Transdermal Contraceptive; The proposed study is a preclinical, multi-site trial comparing the short-term effects of oral and non-oral ethinyl estradiol on the GH/IGF-1 axis and bone metabolism. Using a prospective repeated measures design, we will test the effects of 2 cycles of a transdermal contraceptive (Xulane) on the GH/IGF-1 axis.; Other Names: Xulane
Experimental: Contraceptive Vaginal Ring (CVR) Participants in the CVR group (NuvaRing - 15µg/d EE/120µg/d etonogestrel) will insert a vaginal ring into the vagina on Day 1 of the intervention. The vaginal ring will be removed and discarded after 3 weeks of continuous use (days 1-21 of continuous use and removed on day 22). There will be one week (days 22-28) that will be ring-free. A new ring will be inserted for days 29-49. On day 50, the second ring will be removed, and a third ring will be immediately inserted into the vagina (if the post-study testing is still occurring). The third ring will remain in the vagina for the last week of the post-study period (days 50-56). As soon as the post-study testing is complete, subjects will remove the ring.	Drug: Contraceptive Vaginal Ring; The proposed study is a preclinical, multi-site trial comparing the short-term effects of oral and non-oral ethinyl estradiol on the GH/IGF-1 axis and bone metabolism. Using a prospective repeated measures design, we will test the effects of 2 cycles of vaginal ring contraceptive (Nuva Ring) on the GH/IGF-1 axis.; Other Names: Nuva Ring
No Intervention: Control Group The Control group will complete all procedures with the exception of contraceptive therapy.

Outcome Measures

Primary Outcome Measures

1. Changes in Insulin-like Growth Factor-1 (IGF-1), IGF Binding Proteins (IGFBP-1, IGFBP-3), and Acid Labile Subunit (ALS) [Baseline and post-49 days of contraceptive therapy]

   Changes in serially-sampled fasting serum concentrations of insulin-like growth factor-1 (IGF-1) before and after 49 days of contraceptive therapy. Data were only collected for IGF-1 levels, no assays were performed for IGFBP-1, IGFBP-3, and acid labile subunit (ALS) and no raw data were collected due to insufficient funds.

Secondary Outcome Measures

1. Changes in Bone Turnover Markers [Baseline and post-49 days of contraceptive therapy]

   Changes in serially-sampled fasting serum concentrations of markers of bone formation (osteocalcin, P1NP) and bone resorption (NTx, and CTx) before and after contraceptive therapy.

2. Changes in GH-stimulated IGF-1 Secretion [49 days of contraceptive therapy]

   Changes in IGF-1, IGFBP-1, IGFBP-3,and ALS in response to exogenously administered GH before and after contraceptive therapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 30 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Female

2. Age 18-30 yrs

3. BMI 18-29 kg/m2

4. Non-smoking

5. Not using hormonal contraceptives for at least 6 months prior

6. Not currently pregnant nor intending to become pregnant in the next 6 months

7. Not lactating

8. No apparent metabolic, endocrine, musculoskeletal, or severe psychiatric disease

9. Willing to adhere to maintenance of current exercise training and diet and remain weight stable (±2 kg) during study

10. Variable physical activity acceptable, but mode must be primarily weight bearing

11. At least 9 menses in past 12 months

12. Willing to quit taking any current nutritional supplements and take Calcium and Vitamin D supplements for the duration of the study.

13. If 21 or older, a normal Pap smear must be confirmed.

Exclusion Criteria:

1. Non-weight bearing exercise as primary mode of physical activity

2. Known or suspected metabolic or endocrine disease

3. Pregnant

4. Currently consuming large amounts of soy products

5. Regular consumption of grapefruit juice

6. Current clinical eating disorder or other axis 1 psychiatric or bipolar disorders

7. Oral or hormonal contraceptive use in the last 6 months

8. Currently amenorrheic

9. Hyperparathyroidism

10. Liver or renal disease

11. Evidence of malabsorption or skeletal disorder

12. Thyroid abnormalities (controlled hypothyroidism acceptable)

13. Chronic use of non-steroidal anti-inflammatory drugs (NSAIDS)

14. Taking medications known to have interactions with contraceptive therapy

15. Division I Athlete, on or off season

16. Other Exclusion Criteria proposed by the World Health Organization COC Contraindications (Grossman, 2011)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Women's Health and Exercise Laboratories, The Pennsylvania State University	University Park	Pennsylvania	United States	16802

Sponsors and Collaborators

• Penn State University
• Massachusetts General Hospital
• Purdue University

Investigators

• Principal Investigator: Mary Jane De Souza, PhD, The Pennsylvania State University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 15, 2016

More Information

Publications

• Grossman D, White K, Hopkins K, Amastae J, Shedlin M, Potter JE. Contraindications to combined oral contraceptives among over-the-counter compared with prescription users. Obstet Gynecol. 2011 Mar;117(3):558-565. doi: 10.1097/AOG.0b013e31820b0244.

• Responsible Party: Mary Jane DeSouza, Professor of Kinesiology and Physiology, Penn State University
• ClinicalTrials.gov Identifier: NCT02367833
• Other Study ID Numbers: STUDY00000053
• First Posted: Feb 20, 2015
• Last Update Posted: Mar 9, 2020
• Last Verified: Feb 1, 2020

• Keywords provided by Mary Jane DeSouza, Professor of Kinesiology and Physiology, Penn State University: Insulin-like growth factor-1; Combined oral contraceptive; Contraceptive Vaginal Ring; Transdermal Contraceptive
• Additional relevant MeSH terms: Bone Diseases; Contraceptive Agents; NuvaRing; Contraceptives, Oral; Contraceptives, Oral, Combined

Study Results

Participant Flow

Recruitment Details	Participants were recruited from the Penn State University and Purdue University campuses from January 2015 to June 2016.
Pre-assignment Detail	A total of 60 participants enrolled in the study and 34 participants did not pass the screening phase.

Arm/Group Title	Combined Oral Contraceptives (COC)	Contraceptive Vaginal Ring (CVR)	Control Group
Arm/Group Description	Apri (or generic equivalent - Reclipsen) (30µg/d EE, 150 µg/d desogestrel) is a monophasic dosing regimen of 21 active and 7 placebo pills. On Day 1 of the Intervention, participants in the COC group will begin taking the COC pill. Each participant in this group will ingest active pills from the first pack each day for the first 21 days. Pills ingested on days 22 through 28 are placebo pills. A second pill pack will begin on day 29 and pills with active ingredients will be ingested from the second pack each day for days 29-49. On day 50, the participants will immediately begin a 3rd pill pack, if the post-study testing is still occurring, and will ingest a pill with active ingredients from the third pack for days 50-56 (or for as long as the post-study testing is occurring).	Participants in the CVR group (NuvaRing - 15µg/d EE/120µg/d etonogestrel) will insert a vaginal ring into the vagina on Day 1 of the intervention. The vaginal ring will be removed and discarded after 3 weeks of continuous use (days 1-21 of continuous use and removed on day 22). There will be one week (days 22-28) that will be ring-free. A new ring will be inserted for days 29-49. On day 50, the second ring will be removed, and a third ring will be immediately inserted into the vagina (if the post-study testing is still occurring). The third ring will remain in the vagina for the last week of the post-study period (days 50-56). As soon as the post-study testing is complete, subjects will remove the ring.	The Control group will complete all procedures with the exception of contraceptive therapy.
Period Title: Overall Study
STARTED	9	9	8
COMPLETED	8	8	8
NOT COMPLETED	1	1	0

Baseline Characteristics

Arm/Group Title	Control Group	Combined Oral Contraceptives (COC)	Contraceptive Vaginal Ring (CVR)	Total
Arm/Group Description	The Control group will complete all procedures with the exception of contraceptive therapy.	Apri (or generic equivalent - Reclipsen) (30µg/d EE, 150 µg/d desogestrel) is a monophasic dosing regimen of 21 active and 7 placebo pills. On Day 1 of the Intervention, participants in the COC group will begin taking the COC pill. Each participant in this group will ingest active pills from the first pack each day for the first 21 days. Pills ingested on days 22 through 28 are placebo pills. A second pill pack will begin on day 29 and pills with active ingredients will be ingested from the second pack each day for days 29-49. On day 50, the participants will immediately begin a 3rd pill pack, if the post-study testing is still occurring, and will ingest a pill with active ingredients from the third pack for days 50-56 (or for as long as the post-study testing is occurring).	Participants in the CVR group (NuvaRing - 15µg/d EE/120µg/d etonogestrel) will insert a vaginal ring into the vagina on Day 1 of the intervention. The vaginal ring will be removed and discarded after 3 weeks of continuous use (days 1-21 of continuous use and removed on day 22). There will be one week (days 22-28) that will be ring-free. A new ring will be inserted for days 29-49. On day 50, the second ring will be removed, and a third ring will be immediately inserted into the vagina (if the post-study testing is still occurring). The third ring will remain in the vagina for the last week of the post-study period (days 50-56). As soon as the post-study testing is complete, subjects will remove the ring.	Total of all reporting groups
Overall Participants	8	8	8	24
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	23.6	22.3	23.1	23
Sex: Female, Male (Count of Participants)
Female	8 100%	8 100%	8 100%	24 100%
Male	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White/Caucasian	5 62.5%	5 62.5%	5 62.5%	15 62.5%
Asian	1 12.5%	1 12.5%	0 0%	2 8.3%
African American/Black	0 0%	0 0%	1 12.5%	1 4.2%
Latin American	0 0%	0 0%	1 12.5%	1 4.2%
Other	2 25%	2 25%	1 12.5%	5 20.8%
Region of Enrollment (participants) [Number]
United States	8 100%	8 100%	8 100%	24 100%

Outcome Measures

1. Primary Outcome

Title	Changes in Insulin-like Growth Factor-1 (IGF-1), IGF Binding Proteins (IGFBP-1, IGFBP-3), and Acid Labile Subunit (ALS)
Description	Changes in serially-sampled fasting serum concentrations of insulin-like growth factor-1 (IGF-1) before and after 49 days of contraceptive therapy. Data were only collected for IGF-1 levels, no assays were performed for IGFBP-1, IGFBP-3, and acid labile subunit (ALS) and no raw data were collected due to insufficient funds.
Time Frame	Baseline and post-49 days of contraceptive therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control Group	Combined Oral Contraceptives (COC)	Contraceptive Vaginal Ring (CVR)
Arm/Group Description	The Control group will complete all procedures with the exception of contraceptive therapy.	Apri (or generic equivalent - Reclipsen) (30µg/d EE, 150 µg/d desogestrel) is a monophasic dosing regimen of 21 active and 7 placebo pills. On Day 1 of the Intervention, participants in the COC group will begin taking the COC pill. Each participant in this group will ingest active pills from the first pack each day for the first 21 days. Pills ingested on days 22 through 28 are placebo pills. A second pill pack will begin on day 29 and pills with active ingredients will be ingested from the second pack each day for days 29-49. On day 50, the participants will immediately begin a 3rd pill pack, if the post-study testing is still occurring, and will ingest a pill with active ingredients from the third pack for days 50-56 (or for as long as the post-study testing is occurring).	Participants in the CVR group (NuvaRing - 15µg/d EE/120µg/d etonogestrel) will insert a vaginal ring into the vagina on Day 1 of the intervention. The vaginal ring will be removed and discarded after 3 weeks of continuous use (days 1-21 of continuous use and removed on day 22). There will be one week (days 22-28) that will be ring-free. A new ring will be inserted for days 29-49. On day 50, the second ring will be removed, and a third ring will be immediately inserted into the vagina (if the post-study testing is still occurring). The third ring will remain in the vagina for the last week of the post-study period (days 50-56). As soon as the post-study testing is complete, subjects will remove the ring.
Measure Participants	8	8	8
Baseline IGF-1 Concetration	220.6 (14.8)	228.7 (13.6)	197.1 (15.2)
Post-Therapy IGF-1 Concentration	221.4 (11.5)	185.9 (10.3)	175.2 (11.1)

2. Secondary Outcome

Title	Changes in Bone Turnover Markers
Description	Changes in serially-sampled fasting serum concentrations of markers of bone formation (osteocalcin, P1NP) and bone resorption (NTx, and CTx) before and after contraceptive therapy.
Time Frame	Baseline and post-49 days of contraceptive therapy

Outcome Measure Data

Analysis Population Description

No data was collected due to insufficient funds.

Arm/Group Title	Control Group	Combined Oral Contraceptives (COC)	Contraceptive Vaginal Ring (CVR)
Arm/Group Description	The Control group will complete all procedures with the exception of contraceptive therapy.	Apri (or generic equivalent - Reclipsen) (30µg/d EE, 150 µg/d desogestrel) is a monophasic dosing regimen of 21 active and 7 placebo pills. On Day 1 of the Intervention, participants in the COC group will begin taking the COC pill. Each participant in this group will ingest active pills from the first pack each day for the first 21 days. Pills ingested on days 22 through 28 are placebo pills. A second pill pack will begin on day 29 and pills with active ingredients will be ingested from the second pack each day for days 29-49. On day 50, the participants will immediately begin a 3rd pill pack, if the post-study testing is still occurring, and will ingest a pill with active ingredients from the third pack for days 50-56 (or for as long as the post-study testing is occurring).	Participants in the CVR group (NuvaRing - 15µg/d EE/120µg/d etonogestrel) will insert a vaginal ring into the vagina on Day 1 of the intervention. The vaginal ring will be removed and discarded after 3 weeks of continuous use (days 1-21 of continuous use and removed on day 22). There will be one week (days 22-28) that will be ring-free. A new ring will be inserted for days 29-49. On day 50, the second ring will be removed, and a third ring will be immediately inserted into the vagina (if the post-study testing is still occurring). The third ring will remain in the vagina for the last week of the post-study period (days 50-56). As soon as the post-study testing is complete, subjects will remove the ring.
Measure Participants	0	0	0

3. Secondary Outcome

Title	Changes in GH-stimulated IGF-1 Secretion
Description	Changes in IGF-1, IGFBP-1, IGFBP-3,and ALS in response to exogenously administered GH before and after contraceptive therapy.
Time Frame	49 days of contraceptive therapy

Outcome Measure Data

Analysis Population Description

No data was collected due to insufficient funds.

Arm/Group Title	Control Group	Combined Oral Contraceptives (COC)	Contraceptive Vaginal Ring (CVR)
Arm/Group Description	The Control group will complete all procedures with the exception of contraceptive therapy.	Apri (or generic equivalent - Reclipsen) (30µg/d EE, 150 µg/d desogestrel) is a monophasic dosing regimen of 21 active and 7 placebo pills. On Day 1 of the Intervention, participants in the COC group will begin taking the COC pill. Each participant in this group will ingest active pills from the first pack each day for the first 21 days. Pills ingested on days 22 through 28 are placebo pills. A second pill pack will begin on day 29 and pills with active ingredients will be ingested from the second pack each day for days 29-49. On day 50, the participants will immediately begin a 3rd pill pack, if the post-study testing is still occurring, and will ingest a pill with active ingredients from the third pack for days 50-56 (or for as long as the post-study testing is occurring).	Participants in the CVR group (NuvaRing - 15µg/d EE/120µg/d etonogestrel) will insert a vaginal ring into the vagina on Day 1 of the intervention. The vaginal ring will be removed and discarded after 3 weeks of continuous use (days 1-21 of continuous use and removed on day 22). There will be one week (days 22-28) that will be ring-free. A new ring will be inserted for days 29-49. On day 50, the second ring will be removed, and a third ring will be immediately inserted into the vagina (if the post-study testing is still occurring). The third ring will remain in the vagina for the last week of the post-study period (days 50-56). As soon as the post-study testing is complete, subjects will remove the ring.
Measure Participants	0	0	0

Adverse Events

Time Frame	Adverse event data were collected during period of study enrollment through study completion, a period of approximately 4 months.
Arm/Group Title	Control Group		Combined Oral Contraceptives (COC)		Contraceptive Vaginal Ring (CVR)
Arm/Group Description	The Control group will complete all procedures with the exception of contraceptive therapy.		Apri (or generic equivalent - Reclipsen) (30µg/d EE, 150 µg/d desogestrel) is a monophasic dosing regimen of 21 active and 7 placebo pills. On Day 1 of the Intervention, participants in the COC group will begin taking the COC pill. Each participant in this group will ingest active pills from the first pack each day for the first 21 days. Pills ingested on days 22 through 28 are placebo pills. A second pill pack will begin on day 29 and pills with active ingredients will be ingested from the second pack each day for days 29-49. On day 50, the participants will immediately begin a 3rd pill pack, if the post-study testing is still occurring, and will ingest a pill with active ingredients from the third pack for days 50-56 (or for as long as the post-study testing is occurring).		Participants in the CVR group (NuvaRing - 15µg/d EE/120µg/d etonogestrel) will insert a vaginal ring into the vagina on Day 1 of the intervention. The vaginal ring will be removed and discarded after 3 weeks of continuous use (days 1-21 of continuous use and removed on day 22). There will be one week (days 22-28) that will be ring-free. A new ring will be inserted for days 29-49. On day 50, the second ring will be removed, and a third ring will be immediately inserted into the vagina (if the post-study testing is still occurring). The third ring will remain in the vagina for the last week of the post-study period (days 50-56). As soon as the post-study testing is complete, subjects will remove the ring.
All Cause Mortality
	Control Group		Combined Oral Contraceptives (COC)		Contraceptive Vaginal Ring (CVR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/9 (0%)		0/9 (0%)
Serious Adverse Events
	Control Group		Combined Oral Contraceptives (COC)		Contraceptive Vaginal Ring (CVR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/9 (0%)		0/9 (0%)
Other (Not Including Serious) Adverse Events
	Control Group		Combined Oral Contraceptives (COC)		Contraceptive Vaginal Ring (CVR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/9 (0%)		0/9 (0%)

Limitations/Caveats

[Not Specified]

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.