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

• ClinicalTrials.gov Identifier: NCT00131885
• Recruitment Status: Completed
• First Posted: August 19, 2005
• Results First Posted: June 9, 2010
• Last Update Posted: August 11, 2015
• Sponsor: University of Utah
• Collaborator: National Center for Complementary and Integrative Health (NCCIH)
• Information provided by (Responsible Party): Patricia Murphy, University of Utah

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 (Clinical Trial)
• 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: August 2005
• Actual Primary Completion Date: May 2008
• Actual Study Completion Date: May 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) [ 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 ]

   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). [ 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 ]

   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 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 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 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 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

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

Criteria

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

United States, Utah

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

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. doi: 10.1016/j.contraception.2004.11.004.

• Responsible Party: Patricia Murphy, Professor, University of Utah
• ClinicalTrials.gov Identifier: NCT00131885
• Other Study ID Numbers: 13430; R21AT002297 ( U.S. NIH Grant/Contract )
• First Posted: August 19, 2005
• Results First Posted: June 9, 2010
• Last Update Posted: August 11, 2015
• Last Verified: July 2015

Keywords provided by Patricia Murphy, University of Utah:

Menstruation; Complementary Therapies; Pharmacokinetics; Hypericum; St. John's wort; Levonorgestrel; Women

Additional relevant MeSH terms:

Levonorgestrel; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Physiological Effects of Drugs; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Contraceptives, Oral