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

Phase 4

Completed

Conditions: Bone; Disorder, Development and Growth

Interventions: Drug: Transdermal Contraceptive
Drug: Combined Oral Contraceptive
Drug: Contraceptive Vaginal Ring

Registration Number: NCT02367833

Lead Sponsor: Penn State University

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 60

Inclusion Criteria

Female
Age 18-30 yrs
BMI 18-29 kg/m2
Non-smoking
Not using hormonal contraceptives for at least 6 months prior
Not currently pregnant nor intending to become pregnant in the next 6 months
Not lactating
No apparent metabolic, endocrine, musculoskeletal, or severe psychiatric disease
Willing to adhere to maintenance of current exercise training and diet and remain weight stable (±2 kg) during study
Variable physical activity acceptable, but mode must be primarily weight bearing
At least 9 menses in past 12 months
Willing to quit taking any current nutritional supplements and take Calcium and Vitamin D supplements for the duration of the study.
If 21 or older, a normal Pap smear must be confirmed.

Exclusion Criteria

Non-weight bearing exercise as primary mode of physical activity
Known or suspected metabolic or endocrine disease
Pregnant
Currently consuming large amounts of soy products
Regular consumption of grapefruit juice
Current clinical eating disorder or other axis 1 psychiatric or bipolar disorders
Oral or hormonal contraceptive use in the last 6 months
Currently amenorrheic
Hyperparathyroidism
Liver or renal disease
Evidence of malabsorption or skeletal disorder
Thyroid abnormalities (controlled hypothyroidism acceptable)
Chronic use of non-steroidal anti-inflammatory drugs (NSAIDS)
Taking medications known to have interactions with contraceptive therapy
Division I Athlete, on or off season
Other Exclusion Criteria proposed by the World Health Organization COC Contraindications (Grossman, 2011)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Transdermal Contraceptive (TDC)	Transdermal Contraceptive	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.
Combined Oral Contraceptives (COC)	Combined Oral Contraceptive	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).
Contraceptive Vaginal Ring (CVR)	Contraceptive Vaginal Ring	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.