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

Bone; Disorder, Development and Growth Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02367833
• Other study ID #: STUDY00000053
• Status: Completed
• Phase: Phase 4
• Start date: January 2015
• Est. completion date: December 2018

Study information

• Verified date: February 2020
• Source: Penn State University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: December 2018
• Est. primary completion date: December 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 30 Years

Eligibility

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)

Related Conditions & MeSH terms

• Bone Diseases
• Bone; Disorder, Development and Growth

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	Women's Health and Exercise Laboratories, The Pennsylvania State University	University Park	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
Penn State University	Massachusetts General Hospital, Purdue University

Country where clinical trial is conducted

United States, 

References & Publications (1)

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):558-65. doi: 10.1097/AOG.0b013e31820b0244. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline and post-49 days of contraceptive therapy
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.	Baseline and post-49 days of contraceptive therapy
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.	49 days of contraceptive therapy