Women’s Health Update, a new feature in Holistic Primary Care, will explore the implications of recent clinical studies relevant to the practice of holistic medicine for women’s health issues. Many women are using herbal medicines, nutraceuticals and conventional pharmaceuticals, sometimes in combination. It is essential that we as physicians understand the strengths and drawbacks of each treatment approach, so we can help our patients optimize their health with the least risk of adverse effects.
Antibiotic Use May Influence Risk of Breast Cancer
The Journal of the American Medical Association recently published a troubling study suggesting that antibiotic exposure is associated with increased risk of breast cancer.
The case-control study involved 10,219 women enrolled in Group Health Cooperative (GHC), a Washington state managed care organization. In this cohort, there were 2,266 cases of primary invasive breast cancer, and 385 cases of in situ breast cancer. All of these women had been seen continuously for at least 1 year prior to the cancer diagnosis.
The age and race-matched control subjects were randomly selected from GHC’s databases. The cancer and control groups were similar with respect to length of GHC enrollment, pharmacy status, parity, hysterectomy status, age at menopause, and ever-use of postmenopausal hormones.
Data on antibiotic use were obtained from the Cooperative’s pharmacy database. The investigators compared the two groups in terms of total number of days of antibiotic use, and total number of antibiotic prescriptions per woman. A total of 110,191 antibiotic prescriptions were dispensed to the participants in aggregate. Duration of antibiotic use ranged from 0 to 7,600 days.
For all classes of antibiotics together, increased total days of usage was associated with increased risk of breast cancer. There was a 2.07-fold increase in breast cancer risk (range 1.48–2.89) among women using antibiotics for a total of 1,001 days or more. The odds ratio for breast cancer showed a clear linear correlation with exposure. For women using antibiotics for 1–50 days, the odds ratio was 1.45; for 51–100 days, the odds ratio was 1.53; for 101–500 days, it increased to 1.68, and for 501–1,000 days, it increased to 2.14. Antibiotic use was also associated with increased risk of fatal breast cancer.
There were some differences between antibiotic classes: women who used tetracycline or macrolide antibiotics for acne or rosacea for at least 50 days, did not have an increased risk.
There were also some differences between the cancer and control groups: the women with breast cancers had higher education levels, more healthcare visits, and were more likely to be pre-menopausal. They were more likely to have used oral contraceptives, and had filled more than 25 postmenopausal hormone prescriptions. Breast cancer cases were also more likely than controls to have reached menarche before age 11, to have had their first children after age 30, to have higher body mass indices, first-degree relatives with breast cancer, and higher mammographic breast density.
Among those women who were diagnosed with breast cancer, an increasing number of total antibiotic prescriptions was associated with being older, an increased number of healthcare visits, greater parity, higher BMI, prior hysterectomy, use of postmenopausal HRT, and higher postmenopausal HRT prescriptions (Velicer C, Heckbert S, Lampe J, et al. Antibiotic use in relation to the risk of breast cancer. JAMA. 2004; 291:827–835).
Commentary: The notion that antibiotic use may increase risk of breast cancer was first proposed several decades ago, and it appears plausible when one considers the effects of antibiotics on intestinal flora. Antibiotics alter gut flora and thereby reduce the ability of endogenous “friendly” bacteria to metabolize phytochemicals into compounds that may offer protection against cancer. Antibiotic use also disrupts estrogen metabolism by the intestinal microflora. Even though this may result in lower levels of circulating estrogens, it may also alter estrogen metabolites, and adversely effect immune function and inflammation by increasing production of prostaglandin E2 and over-expression of COX2.
It may be that antibiotics somehow adversely affect endogenous protective mechanisms that normally prevent women from getting breast cancer. Alternatively, the increased cancer risk may reflect weakened immune function in women who need to take antibiotics for frequent infectious conditions.
I’m sure holistically-minded practitioners and their patients do not need any more reasons to limit the prescribing of antibiotics, but here we have it, perhaps the most significant reason yet.
Does St. John’s Wort Reduce Efficacy of Oral Contraceptives?
Two new studies shed some additional light on earlier case reports and theoretical suspicions that St. John’s Wort (Hypericum perforatum), a popular herb for depression, may interfere with oral contraceptive pills (OCP). St. John’s Wort, like several other herbs, contains compounds that induce cytochrome P450 (CYP) 3A enzymes, therefore suggesting that this herb may reduce efficacy of OCPs and other drugs metabolized via the P450 enzyme pathways.
Pharmacologists at Wishard Memorial Hospital, Indianapolis, tested the effect of St. John’s Wort on Ortho-Novum 1/35, an OCP containing ethinyl estradiol and norethindrone. Twelve healthy reproductive aged women had been using Ortho-Novum for three consecutive menstrual cycles. During the second and third cycles, they received 300 mg of St. John’s Wort, thrice daily. The investigators looked at serum concentrations of ethinyl estradiol, norethindrone a, follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone and IV and oral midazolam. They also gathered data on breakthrough bleeding.
Use of St. John’s Wort with the OCP was associated with a significant increase in clearance of norethindrone, and a significant reduction in the half-life of ethinyl estradiol. The herb significantly increased oral clearance of midazolam, but the systemic clearance was stable. FSH, LH, and progesterone were not significantly affected by St. John’s Wort. Two women experienced breakthrough bleeding in the control cycle; this increased to seven during the St. John’s Wort cycles (Hall S, et al. The interaction between St. John’s Wort and an oral contraceptive. Clin Pharmacol Ther. 2003; 74:525–535).
In the second study, researchers at the University Clinic, Basel, Switzerland, evaluated eighteen healthy premenopausal women on a low dose OCP containing 0.02 mg ethinyl estradiol and 0.150 desogestrel either alone during a control cycle, or combined with St. John’s Wort, 300 mg, twice daily (cycle A) or thrice daily (cycle B). FSH, serum estradiol, progesterone levels and pelvic ultrasounds were tested as a measure of ovarian activity. OCP pharmacokinetics and incidents of breakthrough bleeding were assessed.
When the women took St. John’s Wort with their OCPs, there was no significant change in follicle maturation, serum estradiol, or progesterone levels compared with OCP alone. However, 13 of 17 women had intermenstrual bleeding during cycle A and this increased to 15 of 17 during cycle B. Only 6 of 17 had breakthrough bleeding during OCP alone (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).
Commentary: St. John’s Wort does cause a change of ethinyl estradiol-norethindrone metabolism consistent with increased CYP3A activity, and there is an increase in breakthrough bleeding when the herb is taken on top of OCPs. However, when Hall and colleagues measured hyperforin, a marker compound in St. John’s Wort, there was a surprising lack of significant association between hyperforin levels and progesterone serum concentration, breakthrough bleeding rate, or oral clearance of midazolam.
Given the small size of the Hall study, and subject variability, it is difficult to draw definitive conclusions about the pharmacokinetics of the herb’s interaction with OCPs. The only statistically significant results were in the oral clearance of norethindrone and the half-life of ethinyl estradiol, and even these differences were not statistically significant for the study group as a whole.
In the Pfrunder study, there was no evidence of ovulation when St. John’s Wort was taken with an OCP, despite increased intracyclic bleeding. Likewise, there were no changes in blood FSH, estradiol or progesterone. Blood work and pelvic ultrasounds showed no evidence that 300 mg of St. John’s Wort increased ovulation, at least when taken twice or thrice daily. Although there was no change in estradiol levels, there was a significant decrease in desogestrel.
So while neither study showed that St. John’s Wort caused complete failure of the OCP (i.e. Ovulation or pregnancy), both confirm that this herb induces CYP3A4, and both show increased breakthrough bleeding. Since this is a common cause of noncompliance with OCPs, it is important to counsel women to expect breakthrough bleeding if they combine this herb with OCPs.
There may be subgroups of patients who react more strongly to CYP3A inducers, and they may be at a greater risk for adverse interactions or frank OC failures. Based on these two studies, it seems generally prudent to discourage co-use of OCPs and St. John’s Wort, or at least adding a barrier contraceptive if a woman does choose to combine them.
