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

• Sponsor: University of Utah (Other)
• Overall Status: Completed
• CT.gov ID: NCT00131885
• Collaborator: National Center for Complementary and Integrative Health (NCCIH) (NIH)
• Enrollment: 36
• Location: 1
• Arms: 4
• Duration (Months): 33
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Contraception	Dietary Supplement: Placebo Control (Placebo Herb); Dietary Supplement: St. John's Wort; Drug: Levonorgestrel	Phase 4

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: Effects of St. John's Wort on Levonorgestrel
• Study Start Date: Aug 1, 2005
• Actual Primary Completion Date: May 1, 2008
• Actual Study Completion Date: May 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Levonorgestrel 1.5 with Placebo Herb 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); Placebo herb three times daily (ground cellulose) for 4-6 weeks; Drug: Levonorgestrel; Levonorgestrel in a single oral dose
Active Comparator: Levonorgestrel 1.5 with SJW 900 mg 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; St. John's Wort (Hypericum perforatum) orally or 4-6 weeks; Drug: Levonorgestrel; Levonorgestrel in a single oral dose
Active Comparator: Levonorgestrel 2.25 with SJW 900 mg 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; St. John's Wort (Hypericum perforatum) orally or 4-6 weeks; Drug: Levonorgestrel; Levonorgestrel in a single oral dose
Active Comparator: Levonorgestrel 1.5 with SJW 1500 mg 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; St. John's Wort (Hypericum perforatum) orally or 4-6 weeks; Drug: Levonorgestrel; Levonorgestrel in a single oral dose

Outcome Measures

Primary Outcome Measures

1. 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) [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]

   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.

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). [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]

   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.

3. Clearance (L/hr) of Levonorgestrel Over 24 Hours for Each Dosage Group and Each Study Session. [Time Frame: Time 1 (pre-intervention baseline) and Time 2 (following a 6 week intervention)]

   Average and standard deviation for Clearance (L/hr) of Levonorgestrel study for each dosage group and each study session.

Secondary Outcome Measures

1. Mean Levels of Follicle-stimulating Hormone Drawn at Weekly Intervals Until Next Menses [Time Frame: Time 1 (pre-intervention baseline) and Time 2 (following a 6 week intervention)]

   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).

2. Mean Levels of Estradiol-17b (E2) Drawn at Weekly Intervals Until Next Menses [Time Frame: Time 1 (pre-intervention baseline) and Time 2 (following a 6 week intervention)]

   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).

3. Mean Levels of Luteinizing Hormone, Drawn at Weekly Intervals Until Next Menses [Time Frame: Time 1 (pre-intervention baseline) and Time 2 (following a 6 week intervention)]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 30 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Utah	Salt Lake City	Utah	United States	84112

Sponsors and Collaborators

• University of Utah
• National Center for Complementary and Integrative Health (NCCIH)

Investigators

• Principal Investigator: Patricia A. Murphy, DrPH, College of Nursing, University of Utah

Study Documents (Full-Text)

None provided.

More Information

Publications

• Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL. Interaction of St. John's Wort with oral contraceptives: effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception. 2005 Jun;71(6):402-8.

• Responsible Party: Patricia Murphy, Professor, University of Utah
• ClinicalTrials.gov Identifier: NCT00131885
• Other Study ID Numbers: 13430; R21AT002297
• First Posted: Aug 19, 2005
• Last Update Posted: Aug 11, 2015
• Last Verified: Jul 1, 2015

• Keywords provided by Patricia Murphy, Professor, University of Utah: Menstruation; Complementary Therapies; Pharmacokinetics; Hypericum; St. John's wort; Levonorgestrel; Women
• Additional relevant MeSH terms: Levonorgestrel

Study Results

Participant Flow

Recruitment Details	Eligible participants were recruited via local advertising.
Pre-assignment Detail	No enrolled participants were excluded

Arm/Group Title	LNG 1.5 mg Dose, Then Placebo Herb, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Day, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Daily, 2.25 mg LNG Dose	LNG 1.5 mg Dose, Then SJW 1500 ng Day, 1.5 mg LNG
Arm/Group Description	Group 1: one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by placebo herb and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 2: One-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day, and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 3: A one-time oral dose of levonorgestrel 1.5 mg mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day (900 mg total) and a one-time oral dose of levonorgestrel 2.25 mg at the second pharmacokinetic study	Group 4: A one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, then St. John's Wort 300 mg orally five times per day (total 1500 mg daily) and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study
Period Title: Time 1: First Intervention
STARTED	9	9	9	9
COMPLETED	9	9	9	9
NOT COMPLETED	0	0	0	0
Period Title: Time 1: First Intervention
STARTED	9	9	9	9
COMPLETED	9	9	9	9
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	LNG 1.5 mg Dose, Then Placebo Herb, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Day, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Daily, 2.25 mg LNG Dose	LNG 1.5 mg Dose, Then SJW 1500 ng Day, 1.5 mg LNG	Total
Arm/Group Description	Group 1: one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by placebo herb and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 2: One-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day, and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 3: A one-time oral dose of levonorgestrel 1.5 mg mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day (900 mg total) and a one-time oral dose of levonorgestrel 2.25 mg at the second pharmacokinetic study	Group 4: A one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, then St. John's Wort 300 mg orally five times per day (total 1500 mg daily) and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Total of all reporting groups
Overall Participants	9	9	9	9	36
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	9 100%	9 100%	9 100%	9 100%	36 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	23.1 (3.6)	22.4 (3.1)	23 (3.5)	22.9 (3.4)	22.9 (3.3)
Sex: Female, Male (Count of Participants)
Female	9 100%	9 100%	9 100%	9 100%	36 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	9 100%	9 100%	9 100%	9 100%	36 100%

Outcome Measures

1. Primary Outcome

Title	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)
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LNG 1.5 mg Dose, Then Placebo Herb, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Day, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Daily, 2.25 mg LNG Dose	LNG 1.5 mg Dose, Then SJW 1500 ng Day, 1.5 mg LNG
Arm/Group Description	Group 1: one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by placebo herb and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 2: One-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day, and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 3: A one-time oral dose of levonorgestrel 1.5 mg mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day (900 mg total) and a one-time oral dose of levonorgestrel 2.25 mg at the second pharmacokinetic study	Group 4: A one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, then St. John's Wort 300 mg orally five times per day (total 1500 mg daily) and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study
Measure Participants	9	9	9	9
AUC 0-24 hours after drug administration Time 1	586.3 (530.6)	379.4 (201.3)	339.4 (201.2)	253.3 (114.4)
AUC 0-24 hours after drug administration Time 2	478.2 (374.0)	317.4 (171.6)	439.4 (320.1)	210.1 (100.4)

2. Primary Outcome

Title	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).
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LNG 1.5 mg Dose, Then Placebo Herb, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Day, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Daily, 2.25 mg LNG Dose	LNG 1.5 mg Dose, Then SJW 1500 ng Day, 1.5 mg LNG
Arm/Group Description	Group 1: one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by placebo herb and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 2: One-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day, and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 3: A one-time oral dose of levonorgestrel 1.5 mg mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day (900 mg total) and a one-time oral dose of levonorgestrel 2.25 mg at the second pharmacokinetic study	Group 4: A one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, then St. John's Wort 300 mg orally five times per day (total 1500 mg daily) and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study
Measure Participants	9	9	9	9
Ovulation (Progesterone Levels > 3.0 ng/ml) Time 1	3 33.3%	1 11.1%	1 11.1%	3 33.3%
Ovulation (Progesterone Levels >3.0 ng/ml) Time 2	3 33.3%	2 22.2%	2 22.2%	2 22.2%

3. Secondary Outcome

Title	Mean Levels of Follicle-stimulating Hormone Drawn at Weekly Intervals Until Next Menses
Description	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 Frame: Time 1 (pre-intervention baseline) and Time 2 (following a 6 week intervention)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LNG 1.5 mg Dose, Then Placebo Herb, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Day, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Daily, 2.25 mg LNG Dose	LNG 1.5 mg Dose, Then SJW 1500 ng Day, 1.5 mg LNG
Arm/Group Description	Group 1: one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by placebo herb and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 2: One-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day, and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 3: A one-time oral dose of levonorgestrel 1.5 mg mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day (900 mg total) and a one-time oral dose of levonorgestrel 2.25 mg at the second pharmacokinetic study	Group 4: A one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, then St. John's Wort 300 mg orally five times per day (total 1500 mg daily) and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study
Measure Participants	9	9	9	9
FSH, IU/mL, Time 1, week 0	14.9 (5.7)	14.0 (4.8)	15.8 (8.0)	13.9 (4.3)
FSH, IU/mL, Time 1, week 1	14.5 (5.0)	14.7 (4.8)	13.9 (5.2)	13.6 (4.4)
FSH, IU/mL, Time 1, week 2	13.8 (4.2)	13.4 (4.3)	20.4 (12.0)	15.4 (9.9)
FSH, IU/mL, Time 2, week 0	12.9 (3.5)	13.0 (3.6)	17.5 (10.1)	14.7 (4.1)
FSH, IU/mL, Time 2, week 1	11.8 (3.0)	15.9 (5.0)	17.7 (8.8)	13.8 (4.5)
FSH, IU/mL, Time 2, week 2	11.3 (4.4)	14.1 (4.5)	14.8 (4.7)	16.8 (10.1)

4. Primary Outcome

Title	Clearance (L/hr) of Levonorgestrel Over 24 Hours for Each Dosage Group and Each Study Session.
Description	Average and standard deviation for Clearance (L/hr) of Levonorgestrel study for each dosage group and each study session.
Time Frame	Time Frame: Time 1 (pre-intervention baseline) and Time 2 (following a 6 week intervention)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LNG 1.5 mg Dose, Then Placebo Herb, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Day, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Daily, 2.25 mg LNG Dose	LNG 1.5 mg Dose, Then SJW 1500 ng Day, 1.5 mg LNG
Arm/Group Description	Group 1: one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by placebo herb and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 2: One-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day, and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 3: A one-time oral dose of levonorgestrel 1.5 mg mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day (900 mg total) and a one-time oral dose of levonorgestrel 2.25 mg at the second pharmacokinetic study	Group 4: A one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, then St. John's Wort 300 mg orally five times per day (total 1500 mg daily) and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study
Measure Participants	9	9	9	9
Clearance (L/hr) Time 1	4.06 (2.60)	4.93 (2.19)	6.39 (4.23)	6.85 (2.51)
Clearance L/hr Time 2	4.64 (2.44)	5.63 (2.08)	7.68 (4.97)	8.92 (4.60)

5. Secondary Outcome

Title	Mean Levels of Estradiol-17b (E2) Drawn at Weekly Intervals Until Next Menses
Description	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 Frame: Time 1 (pre-intervention baseline) and Time 2 (following a 6 week intervention)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LNG 1.5 mg Dose, Then Placebo Herb, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Day, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Daily, 2.25 mg LNG Dose	LNG 1.5 mg Dose, Then SJW 1500 ng Day, 1.5 mg LNG
Arm/Group Description	Group 1: one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by placebo herb and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 2: One-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day, and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 3: A one-time oral dose of levonorgestrel 1.5 mg mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day (900 mg total) and a one-time oral dose of levonorgestrel 2.25 mg at the second pharmacokinetic study	Group 4: A one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, then St. John's Wort 300 mg orally five times per day (total 1500 mg daily) and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study
Measure Participants	9	9	9	9
Estradiol, pg/mL, Time 1, week 0	133.3 (64.3)	137.2 (76.9)	131.1 (75.0)	103.5 (52.2)
Estradiol, pg/mL, Time 1, week 1	142.2 (90.0)	154.7 (117.1)	138.4 (77.7)	290.6 (34.8)
Estradiol, pg/mL,Time 1, week 2	132.4 (103.9)	107.9 (39.3)	132.6 (73.3)	230.4 (34.2)
Estradiol, pg/mL,Time 2, week 0	134.2 (73.9)	102.0 (44.2)	119.3 (77.9)	123.4 (60.2)
Estradiol, pg/mL,Time 2, week 1	210.7 (227.1)	121.6 (57.5)	113.9 (71.1)	118.0 (86.3)
Estradiol, pg/mL,Time 2, week 2	146.3 (80.5)	192.0 (101.2)	102.9 (75.1)	108.7 (47.6)

6. Secondary Outcome

Title	Mean Levels of Luteinizing Hormone, Drawn at Weekly Intervals Until Next Menses
Description	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 Frame: Time 1 (pre-intervention baseline) and Time 2 (following a 6 week intervention)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LNG 1.5 mg Dose, Then Placebo Herb, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Day, LNG 1.5 mg	LNG 1.5 mg Dose, Then SJW 900 mg Daily, 2.25 mg LNG Dose	LNG 1.5 mg Dose, Then SJW 1500 ng Day, 1.5 mg LNG
Arm/Group Description	Group 1: one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by placebo herb and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 2: One-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day, and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study	Group 3: A one-time oral dose of levonorgestrel 1.5 mg mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day (900 mg total) and a one-time oral dose of levonorgestrel 2.25 mg at the second pharmacokinetic study	Group 4: A one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, then St. John's Wort 300 mg orally five times per day (total 1500 mg daily) and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study
Measure Participants	9	9	9	9
LH, IU/L, Time 1, week 0	24.7 (10.1)	20.9 (10.4)	26.4 (15.7)	25.3 (15.7)
LH, IU/L, Time 1, week 1	35.1 (16.1)	30.2 (21.8)	24.6 (16.3)	25.3 (15.7)
LH, IU/L, Time 1, week 2	36.2 (20.1)	23.1 (14.7)	25.6 (22.1)	23.2 (18.4)
LH IU/L, Time 2, week 0	33.2 (16.5)	28.4 (14.9)	31.9 (27.5)	46.3 (25.8)
LH, IU/L, Time 2, week 1	30.1 (20.0)	27.5 (17.9)	40.0 (46.5)	28.8 (11.4)
LH, IU/L, Time 2, week 2	29.1 (22.5)	27.7 (19.1)	27.7 (19.1)	39.1 (18.0)

Adverse Events

Arm/Group Title	LNG 1.5 mg Dose, Then Placebo Herb, LNG 1.5 mg		LNG 1.5 mg Dose, Then SJW 900 mg Day, LNG 1.5 mg		LNG 1.5 mg Dose, Then SJW 900 mg Daily, 2.25 mg LNG Dose		LNG 1.5 mg Dose, Then SJW 1500 ng Day, 1.5 mg LNG
Arm/Group Description	Group 1: one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by placebo herb and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study		Group 2: One-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day, and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study		Group 3: A one-time oral dose of levonorgestrel 1.5 mg mg at the first pharmacokinetic study, followed by St. John's Wort 300 mg orally three times per day (900 mg total) and a one-time oral dose of levonorgestrel 2.25 mg at the second pharmacokinetic study		Group 4: A one-time oral dose of levonorgestrel 1.5 mg at the first pharmacokinetic study, then St. John's Wort 300 mg orally five times per day (total 1500 mg daily) and a one-time oral dose of levonorgestrel 1.5 mg at the second pharmacokinetic study
All Cause Mortality
	LNG 1.5 mg Dose, Then Placebo Herb, LNG 1.5 mg		LNG 1.5 mg Dose, Then SJW 900 mg Day, LNG 1.5 mg		LNG 1.5 mg Dose, Then SJW 900 mg Daily, 2.25 mg LNG Dose		LNG 1.5 mg Dose, Then SJW 1500 ng Day, 1.5 mg LNG
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	LNG 1.5 mg Dose, Then Placebo Herb, LNG 1.5 mg		LNG 1.5 mg Dose, Then SJW 900 mg Day, LNG 1.5 mg		LNG 1.5 mg Dose, Then SJW 900 mg Daily, 2.25 mg LNG Dose		LNG 1.5 mg Dose, Then SJW 1500 ng Day, 1.5 mg LNG
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/9 (0%)		0/9 (0%)		0/9 (0%)
Other (Not Including Serious) Adverse Events
	LNG 1.5 mg Dose, Then Placebo Herb, LNG 1.5 mg		LNG 1.5 mg Dose, Then SJW 900 mg Day, LNG 1.5 mg		LNG 1.5 mg Dose, Then SJW 900 mg Daily, 2.25 mg LNG Dose		LNG 1.5 mg Dose, Then SJW 1500 ng Day, 1.5 mg LNG
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/9 (0%)		0/9 (0%)		0/9 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.