Beware or Be Blue: Does St. John’s Wort Interfere with Oral Contraceptives?

Source: Hall SD, et al. The interaction between St. John’s wort and an oral contraceptive. Clin Pharmacol Ther 2003;74:525-535.

Abstract: The popular herbal remedy St. John’s wort is an inducer of cytochrome P450 (CYP) 3A enzymes and may reduce the efficacy of oral contraceptives. The researchers evaluated the effect of St. John’s wort on the disposition and efficacy of Ortho-Novum 1/35 (Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ), a popular combination oral contraceptive pill containing ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). Twelve healthy premenopausal women who had been using oral contraception for more than three months received a combination oral contraceptive pill (Ortho-Novum 1/35) for three consecutive 28-day menstrual cycles. During the second and third cycles, the participants received 300 mg St. John’s wort tid. The serum concentrations of ethinyl estradiol (day 7), norethindrone (day 7), follicle-stimulating hormone (days 12-16), luteinizing hormone (days 12-16), progesterone (day 21), and intravenous and oral midazolam (days 22 and 23) were determined in serial blood samples. The incidence of breakthrough bleeding was quantified during the first and third cycles. The researchers found concomitant use of St. John’s wort was associated with a significant increase in the oral clearance of norethindrone and a significant reduction in the half-life of ethinyl estradiol. The oral clearance of midazolam was significantly increased during St. John’s wort administration, but the systemic clearance of midazolam was unchanged. Serum concentrations of follicle-stimulating hormone, luteinizing hormone, and progesterone were not significantly affected by St. John’s wort dosing. Two of the 12 women experienced breakthrough bleeding in the control phase compared with seven of 12 women in the St. John’s wort phase. The oral clearance of midazolam after St. John’s wort dosing was greater in women who had breakthrough bleeding than in those who did not. The authors concluded that St. John’s wort causes an induction of ethinyl estradiol-norethindrone metabolism consistent with increased CYP3A activity. They recommend women taking oral contraceptive pills to be counseled to expect breakthrough bleeding and to consider adding a barrier method of contraception when consuming St. Johns wort.

Source: Pfrunder A, et al. Interaction of St. John’s wort with low-dose oral contraceptive therapy: A randomized controlled trial. Br J Clin Pharmacol 2003;56:683-690.

Abstract: Breakthrough bleeding or even unwanted pregnancies have been reported in women during concomitant therapy with oral contraceptives and St. John’s wort extract. The aim of the study was to investigate the effects of St. John’s wort extract on oral contraceptive therapy with respect to ovarian activity, breakthrough bleeding episodes, and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel. Eighteen healthy females were treated with a low-dose oral contraceptive (0.02 mg ethinyloestradiol, 0.150 mg desogestrel) alone (control cycle) or combined with 300 mg St. John’s wort extract given twice daily (cycle A) or three times daily (cycle B). Ovarian activity was assessed by measuring follicle maturation and serum oestradiol and progesterone concentrations. The number of breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel were assessed under steady-state conditions. The researchers found that during concomitant administration of low-dose oral contraceptive and St. John’s wort, there was no significant change in follicle maturation, serum oestradiol, or progesterone concentrations when compared with oral contraceptive treatment alone. However, significantly more subjects reported intracyclic bleeding during cycles A (13/17 [77%], P < 0.015) and cycle B (15/17 [88%], P < 0.001) than with oral contraceptives alone (6/17 [35%]). The authors concluded there was no evidence of ovulation during low-dose oral contraceptive and St. John’s wort extract combination therapy, but intracyclic bleeding episodes increased. Bleeding irregularities may adversely effect compliance to oral contraceptives and together with St. John’s wort-induced decreases in serum 3-ketodesogestrel concentrations, enhance the risk of unintended pregnancies.

Comments by Mary L. Hardy, MD

Depression in young women is a common and unfortunately under-recognized condition. Women are three times more likely than men to suffer from clinical depression and one in eight women will have at least one episode of depression in her lifetime. Five percent of menstruating women suffer from Premenstrual Dysphoric Disorder (PMDD) and 12 million women annually qualify as depressed in any given year. Despite the relatively high prevalence of this disorder, more than half of the affected women do not seek medical care for this condition. Since there are many reasons women are reluctant to enter the medical care system for depression treatment, this leaves a significant number of reproductive age women looking for treatment options outside conventional medicine.1

St. John’s wort (SJW) is one of the most popular herbal treatments for mild-to-moderate depression, with a large number of clinical trials demonstrating efficacy.2 Although no specific figures exist to estimate the number of young women trying SJW, it is likely to be significant. In February 2000, early reports noted a potential herb-drug interaction between SJW and oral contraceptive pills (OCPs).3 Subsequent pharmacologic studies confirmed that SJW does affect key subtypes of the cytochrome P450 (CYP450) enzyme system, including CYP1A2, 2C9, and 3A4.4 Induction of these key isozymes potentially can affect the metabolism of many drugs, including OCPs. Interactions have been confirmed for indinavir, cyclosporin, and theophyllin. However, these interactions do not uniformly predict actual drug levels as significant variations in individual response exist. Two recent clinical trials have been performed to clarify the effects of SJW on OCPs. These trials represent an attempt to validate anecdotal observations in larger, more clinically relevant settings and, thus, are important for the validation of suspected herb-drug interactions.

In the first trial, 12 healthy women taking a popular combination OCP (Ortho-Novum 1/35) containing ethinyl estradiol (EE) and norethindrone (NE) for three cycles (28 days on medication with one week off medication) were given SJW 300 mg tid during the second and third months of treatment.5 Effects on the pharmacokinetics of both EE and NE were modest and not generally statistically significant. The only statistically significant results seen were a decrease in the oral clearance of NE (P = 0.042) and in the half-life of EE (P = 0.023). Effects of the SJW preparation on the activity of the CYP450 enzyme system were confirmed by the use of a "probe medication," midazolam. By using medications with a known pattern of metabolism in the CYP450 system, the effect of the test material, SJW in this case, can be confirmed. Based on the pattern of levels of midazolam, this SJW preparation caused induction of mainly the intestinal rather than the hepatic CYP450 isozyme CYP3A. Clinically, there was an increase in breakthrough bleeding reported during the SJW phase of the trial, but no change in the blood levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), or progesterone were noted. Interestingly, there was a strongly statistically significant association between higher midazolam clearance and increased incidence of breakthrough bleeding, suggesting (but not establishing) that the rise in breakthrough bleeding was the result of the changes in metabolism at the CYP450 system.

The SJW product used in the trial, identified by brand name, was reported by the authors to contain amounts of hypericin and hyperforin comparable with other standardized SJW preparations. The hyperforin levels also were measured in blood after the second month of SJW use. These levels showed up to a threefold variation among individuals. Although hyperforin is the constituent thought to be responsible for the induction of the CYP3A isozyme, no significant association was established between the levels of hyperforin and progesterone serum concentration, breakthrough bleeding rate, or oral clearance of midazolam. This study was too small and interpersonal variability was too great to demonstrate statistically significant effects on pharmacokinetics of the constituents of a common oral contraceptive medication. However, breakthrough bleeding, a major cause of discontinuation of OCPs, was much more common with SJW use. Even though statistically significant results could not be demonstrated for the group as a whole, based on the broad variation in personal response, there are subgroups of patients who may react more strongly to CYP3A inducers and thus may be at greater risk for contraceptive failure due to SJW use.

A second study performed by a European group, looked at the effects of a SJW preparation at two dosage levels on the pharmacokinetics of a low-dose, fixed combination OCP similar to the material tested in the previous trial.6 Eighteen women were enrolled and first were observed for one control cycle. Next, they were given either a low dose (300 mg bid) or a high dose (300 mg tid) of a SJW product standardized to 0.3% hypericin concentration. The amount of hyperforin in the preparation was not reported. After completion of the first study cycle, subjects were crossed over to the alternate dosage. No washout period was observed. Lack of a washout phase is not the ideal trial design. Not allowing time for the first treatment effect to dissipate may influence the second study period and mean that the two episodes of treatment are not equivalent.

Blood levels of FSH, LH, estrogen, and progesterone were measured both before and after exposure to SJW. In addition, ultrasounds were done to document the presence or absence of ovulation by measuring follicles in the ovary and the thickness of the endometrial wall. After treatment, almost all of the subjects reported episodes of breakthrough bleeding. There were no significant numbers of follicle-like structures reported in the treated patients at either dosage level of SJW. No changes in progesterone or endometrial thickness were noted. Thus, SJW use did not lead to increased rates of ovulation in these test subjects at either dosage level. There were no changes in the estrogenic component of this pill, but there was a highly significant decrease in the amount of 3-ketodesogestrel present after SJW use.

The results of these two trials taken together are very interesting. Both clearly demonstrate that SJW induces CYP3A4 with variable effects on levels of steroid hormones used in two common OCPs. These changes do not seem to lead to ovulation in the small study populations examined here, but they clearly increase the rate of breakthrough bleeding. Also, individual responses to SJW vary significantly enough that certain individuals may be at greater risk of contraceptive failure than the average response of these study patients would predict. Based on these data, it seems prudent to discourage concomitant use of OCPs and SJW, even without proof of increased ovulation.

Dr. Hardy, Medical Director, Cedars-Sinai Integrative Medicine Medical Group, Los Angeles, CA, is on the Editorial Advisory Board of Alternative Therapies in Women’s Health.

References

1. National Mental Health Association. Depression in women. Available at: www.nmha.org/infoctr/factsheets. Accessed Feb. 15, 2004.

2. Linde K, et al. Saint John’s wort for depression: An overview and meta-analysis of randomized clinical trials. Br Med J 1996;313:253-258.

3. Yue QY, et al. Safety of St. John’s wort. Lancet 2000;355:576-577.

4. Wang Z, et al. The effects of St. John’s Wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 2001;70:317-326.

5. Hall SD, et al. The interaction between St. John’s wort and an oral contraceptive. Clin Pharmacol Ther 2003; 74:525-535.

6. Pfrunder A, et al. Interaction of St. John’s wort with low-dose oral contraceptive therapy: A randomized controlled trial. Br J Clin Pharmacol 2003;56:683-690.