Clinical trial NCT02367833: Effects of Oral vs. Non-oral Contraceptives on the GH/IGF-1 Axis
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Bone; Disorder, Development and Growth
Keywords: Insulin-like growth factor-1
Combined oral contraceptive
Contraceptive Vaginal Ring
Transdermal Contraceptive
Lead sponsor: Penn State University
Sponsor class: OTHER
Collaborators: name: Massachusetts General Hospital
name: Purdue University
First posted: 2015-02-20
Enrollment: 60
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 30
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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

Primary outcomes:
measure: Changes in Insulin-like Growth Factor-1 (IGF-1), IGF Binding Proteins (IGFBP-1, IGFBP-3), and Acid Labile Subunit (ALS)
timeFrame: Baseline and post-49 days of contraceptive therapy
Secondary outcomes:
measure: Changes in Bone Turnover Markers
timeFrame: Baseline and post-49 days of contraceptive therapy
measure: Changes in GH-stimulated IGF-1 Secretion
timeFrame: 49 days of contraceptive therapy
Other outcomes:
Locations:
city: University Park
country: United States
facility: Women's Health and Exercise Laboratories, The Pennsylvania State University
state: Pennsylvania
Study officials:
affiliation: The Pennsylvania State University
name: Mary Jane De Souza, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.