Effects of St. John's Wort on the Oral Contraceptive Hormone Levonorgestrel

Study Overview
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Brief Summary
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This study will determine the effects of St. John's wort, a common herbal remedy, on metabolism of the female contraceptive hormone levonorgestrel.

Detailed Description
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In the last decade, St. John's wort has become one of the most commonly used botanicals. Levonorgestrel is a form of progesterone, a female hormone involved in conception. It can be given as both a pill and an injection and is used for contraception and for the treatment of endometriosis. However, evidence suggests that St. John's wort may reduce the effectiveness of the contraceptive hormone levonorgestrel. This study will determine whether interactions between St. John's wort and levonorgestrel reduce the effectiveness of the hormone. This study will also determine whether a higher dose of levonorgestrel will override the effects of St. John's wort. All participants will receive a single dose of levonorgestrel between Days 9 and 12 of their first menstrual cycle after entering this study. Blood and urine collection will occur immediately after the levonorgestrel is given and every week until participants' next menstrual cycle to determine the levels of reproductive hormones in participants' bodies. At the beginning of participants' next menstrual cycle, they will be randomly assigned to one of four groups and receive either St. John's wort or placebo for 6 weeks. Group 1 will receive a placebo; Groups 2 and 3 will receive a standard dose of St. John's wort (900 mg per day); and Group 4 will receive an increased dose of St. John's wort (1500 mg per day). After 6 weeks, Groups 1, 2, and 4 will receive 150 mcg levonorgestrel; and Group 3 will receive 225 mcg levonorgestrel. Blood and urine collection will occur immediately after levonorgestrel is given and every week until participants' next menstrual cycle.

Official Title
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Effects of St. John's Wort on Levonorgestrel

Conditions
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Contraception

Intervention / Treatment
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* Dietary Supplement: Placebo Control (Placebo Herb)
* Dietary Supplement: St. John's Wort
* Drug: Levonorgestrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index (BMI) between 20 and 25 Regular menstrual cycles for at least 3 months prior to study entry Exclusion Criteria: Current use of foods, herbs, vitamins, over-the-counter supplements, or any medications that could alter pharmacokinetics of other drugs Medical contraindications to the use of contraceptives

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Levonorgestrel 1.5 with Placebo Herb<br>This group had baseline pharmacokinetic studies after an oral dose of levonorgestrel (LNG) 1.5 mg, then took a placebo herb daily for 4-6 weeks, during which time pharmacokinetic studies were repeated after an oral dose of LNG 1.5 mg | Dietary Supplement: Placebo Control (Placebo Herb)<br>* Placebo herb three times daily (ground cellulose) for 4-6 weeks<br>Drug: Levonorgestrel<br>* Levonorgestrel in a single oral dose<br>|
| Active Comparator: Levonorgestrel 1.5 with SJW 900 mg<br>This group had baseline pharmacokinetic studies after an oral dose of levonorgestrel (LNG) 1.5 mg, then took St. John's Wort (SJW) 900 mg a Day orally for 4-6 weeks, during which time pharmacokinetic studies were repeated after an oral dose of LNG 1.5 mg | Dietary Supplement: St. John's Wort<br>* St. John's Wort (Hypericum perforatum) orally or 4-6 weeks<br>Drug: Levonorgestrel<br>* Levonorgestrel in a single oral dose<br>|
| Active Comparator: Levonorgestrel 2.25 with SJW 900 mg<br>This group had baseline pharmacokinetic studies after an oral dose of levonorgestrel (LNG) 1.5 mg, then took a St. Johns's Wort 300 mg capsules three times daily for 4-6 weeks, during which time pharmacokinetic studies were repeated after an oral dose of LNG 2.25 mg | Dietary Supplement: St. John's Wort<br>* St. John's Wort (Hypericum perforatum) orally or 4-6 weeks<br>Drug: Levonorgestrel<br>* Levonorgestrel in a single oral dose<br>|
| Active Comparator: Levonorgestrel 1.5 with SJW 1500 mg<br>This group had baseline pharmacokinetic studies after an oral dose of levonorgestrel (LNG) 1.5 mg, then took a St. Johns's Wort 300 mg capsules five times daily for 4-6 weeks, during which time pharmacokinetic studies were repeated after an oral dose of LNG 1.5 mg | Dietary Supplement: St. John's Wort<br>* St. John's Wort (Hypericum perforatum) orally or 4-6 weeks<br>Drug: Levonorgestrel<br>* Levonorgestrel in a single oral dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration Versus Time Curve for 0 to 24 Hours After Drug Administration, Done Between Days 9 and 12 of the Menstrual Cycle at Time 1 (Before) and Time 2 (During Treatment With St. John's Wort or Placebo) | Pharmacokinetic studies were done between Days 9-12 of the menstrual cycle at Time 1 (baseline, before any treatment with herb or placebo), and at Time 2 (intervention, after treatment with herb or placebo). Serum samples drawn at 0, ½, 1, 1½, 2, 3, 4, 6, 8, 12, 16, and 24 hours, following oral administration of a dose of levonorgestrel. Treatment between the two time periods was with St. John's Wort or placebo herb, beginning after the Time 1 (baseline) and continued for 5 weeks until Time 2. Estimates of levonorgestrel clearance were made using a two stage non-compartmental approach to determine individual and group parameters. | Area Under the Concentration versus Time curve for 0 to 24 hours after drug administration, between Days 9 and 12 of the menstrual cycle, done at Time 1 and at Time 2 | 
| Number of Participants With Progesterone Levels Above 3.0 ng/ml at Time 1 (Baseline) and Time 2 (After Intervention With St John's Wort or Placebo). | Serum progesterone levels were drawn at the time of dosing with levonorgestrel and then at weekly intervals until menses occurred. This was done at Time 1 (baseline), and again at Time 2 (after 5 weeks of dosing with St. John's Wort or placebo). Possible ovulation was defined as a serum progesterone >3ng/ml within 2 weeks of Days 9-12 of the menstrual cycle. | Progesterone levels drawn at weekly intervals after dosing with levonorgestrel between Days 9 and 12 of the menstrual cycle, at each time point until menses | 
| Clearance (L/hr) of Levonorgestrel Over 24 Hours for Each Dosage Group and Each Study Session. | Average and standard deviation for Clearance (L/hr) of Levonorgestrel study for each dosage group and each study session. | Time Frame: Time 1 (pre-intervention baseline) and Time 2 (following a 6 week intervention) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Levels of Follicle-stimulating Hormone Drawn at Weekly Intervals Until Next Menses | Descriptive reporting of secondary outcomes of reproductive hormone levels (including FSH, E2, LH). Pharmacokinetic studies were done between Days 9-12 of the menstrual cycle at Time 1 (baseline, before any treatment with herb or placebo), and at Time 2 (intervention, after treatment with herb or placebo). Weekly means are reported for both time periods at week 0 (day of pharmacokinetic study), week 1 (one week after pharmacokinetic study) and week 2 (2 weeks after pharmacokinetic study). | Time Frame: Time 1 (pre-intervention baseline) and Time 2 (following a 6 week intervention) | 
| Mean Levels of Estradiol-17b (E2) Drawn at Weekly Intervals Until Next Menses | Descriptive reporting of secondary outcomes of reproductive hormone levels (including FSH, E2, LH). Pharmacokinetic studies were done between Days 9-12 of the menstrual cycle at Time 1 (baseline, before any treatment with herb or placebo), and at Time 2 (intervention, after treatment with herb or placebo). Weekly means are reported for both time periods at week 0 (day of pharmacokinetic study), week 1 (one week after pharmacokinetic study) and week 2 (2 weeks after pharmacokinetic study). | Time Frame: Time 1 (pre-intervention baseline) and Time 2 (following a 6 week intervention) | 
| Mean Levels of Luteinizing Hormone, Drawn at Weekly Intervals Until Next Menses | Descriptive reporting of secondary outcomes of reproductive hormone levels (including FSH, E2, LH). Pharmacokinetic studies were done between Days 9-12 of the menstrual cycle at Time 1 (baseline, before any treatment with herb or placebo), and at Time 2 (intervention, after treatment with herb or placebo). Weekly means are reported for both time periods at week 0 (day of pharmacokinetic study), week 1 (one week after pharmacokinetic study) and week 2 (2 weeks after pharmacokinetic study). | Time Frame: Time 1 (pre-intervention baseline) and Time 2 (following a 6 week intervention) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Menstruation, Complementary Therapies, Pharmacokinetics, Hypericum, St. John's wort, Levonorgestrel, Women