Bone; Disorder, Development and Growth
Conditions
Keywords
Insulin-like growth factor-1, Combined oral contraceptive, Contraceptive Vaginal Ring, Transdermal Contraceptive
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.
Interventions
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.
DRUGTransdermal 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.
DRUGContraceptive 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.
Sponsors
Massachusetts General Hospital
Purdue University
Penn State University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 30 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the Penn State University and Purdue University campuses from January 2015 to June 2016.
Pre-assignment details
A total of 60 participants enrolled in the study and 34 participants did not pass the screening phase.
Participants by arm
| Arm | Count |
|---|---|
| Control Group The Control group will complete all procedures with the exception of contraceptive therapy. | 8 |
| 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). | 8 |
| 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. | 8 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Control Group | Combined Oral Contraceptives (COC) | Contraceptive Vaginal Ring (CVR) | Total |
|---|---|---|---|---|
| Age, Continuous | 23.6 years | 22.3 years | 23.1 years | 23 years |
| Race/Ethnicity, Customized African American/Black | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Latin American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized White/Caucasian | 5 Participants | 5 Participants | 5 Participants | 15 Participants |
| Region of Enrollment United States | 8 participants | 8 participants | 8 participants | 24 participants |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 8 Participants | 24 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 0 / 8 | 0 / 9 | 0 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 9 | 0 / 9 |
Outcome results
Primary
Changes in Insulin-like Growth Factor-1 (IGF-1), IGF Binding Proteins (IGFBP-1, IGFBP-3), and Acid Labile Subunit (ALS)
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control Group | Changes in Insulin-like Growth Factor-1 (IGF-1), IGF Binding Proteins (IGFBP-1, IGFBP-3), and Acid Labile Subunit (ALS) | Baseline IGF-1 Concetration | 220.6 ng/mL | Standard Error 14.8 |
| Control Group | Changes in Insulin-like Growth Factor-1 (IGF-1), IGF Binding Proteins (IGFBP-1, IGFBP-3), and Acid Labile Subunit (ALS) | Post-Therapy IGF-1 Concentration | 221.4 ng/mL | Standard Error 11.5 |
| Combined Oral Contraceptives (COC) | Changes in Insulin-like Growth Factor-1 (IGF-1), IGF Binding Proteins (IGFBP-1, IGFBP-3), and Acid Labile Subunit (ALS) | Baseline IGF-1 Concetration | 228.7 ng/mL | Standard Error 13.6 |
| Combined Oral Contraceptives (COC) | Changes in Insulin-like Growth Factor-1 (IGF-1), IGF Binding Proteins (IGFBP-1, IGFBP-3), and Acid Labile Subunit (ALS) | Post-Therapy IGF-1 Concentration | 185.9 ng/mL | Standard Error 10.3 |
| Contraceptive Vaginal Ring (CVR) | Changes in Insulin-like Growth Factor-1 (IGF-1), IGF Binding Proteins (IGFBP-1, IGFBP-3), and Acid Labile Subunit (ALS) | Baseline IGF-1 Concetration | 197.1 ng/mL | Standard Error 15.2 |
| Contraceptive Vaginal Ring (CVR) | Changes in Insulin-like Growth Factor-1 (IGF-1), IGF Binding Proteins (IGFBP-1, IGFBP-3), and Acid Labile Subunit (ALS) | Post-Therapy IGF-1 Concentration | 175.2 ng/mL | Standard Error 11.1 |
Secondary
Changes in Bone Turnover Markers
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
Population: No data was collected due to insufficient funds.
Secondary
Changes in GH-stimulated IGF-1 Secretion
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
Population: No data was collected due to insufficient funds.