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

NCT ID: NCT02367833

Last Updated: 2020-03-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-31
• Study Completion Date: 2018-12-31

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.

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.

Conditions

Bone; Disorder, Development and Growth

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

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).

Group Type: EXPERIMENTAL

Combined Oral Contraceptive

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Transdermal Contraceptive

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Contraceptive Vaginal Ring

Intervention Type: DRUG

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.

Control Group

The Control group will complete all procedures with the exception of contraceptive therapy.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Apri (Reclipsen); Xulane; Nuva Ring

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 30 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Massachusetts General Hospital

OTHER

Sponsor Role: collaborator

Purdue University

OTHER

Sponsor Role: collaborator

Penn State University

OTHER

Sponsor Role: lead

Responsible Party

Mary Jane DeSouza

Professor of Kinesiology and Physiology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Mary Jane De Souza, PhD

Role: PRINCIPAL_INVESTIGATOR

The Pennsylvania State University

Locations

Women's Health and Exercise Laboratories, The Pennsylvania State University

University Park, Pennsylvania, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 21343758 (View on PubMed)

Allaway HCM, Misra M, Southmayd EA, Stone MS, Weaver CM, Petkus DL, De Souza MJ. Are the Effects of Oral and Vaginal Contraceptives on Bone Formation in Young Women Mediated via the Growth Hormone-IGF-I Axis? Front Endocrinol (Lausanne). 2020 Jun 16;11:334. doi: 10.3389/fendo.2020.00334. eCollection 2020.

Reference Type: DERIVED

PMID: 32612574 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

STUDY00000053

Identifier Type: -

Identifier Source: org_study_id