The Effect of St. John's Wort on Hot Flashes in Women

Abstract & Commentary

By Judith L. Balk, MD, MPH, FACOG. Dr. Balk is Associate Professor, Magee-Women's Hospital, University of Pittsburgh; she reports no financial relationship to this field of study.

Synopsis: One hundred women with hot flashes, aged 45-55, were randomized to receive St. John's wort (SJW) or placebo for 8 weeks. At 4 weeks, the frequency and severity of the hot flashes were better in the treatment group than in the placebo group, whereas the duration of hot flashes was the same in both groups. At 8 weeks, severity, frequency, and duration were better in the treatment group than in the placebo group. However, both groups improved over time, relative to baseline.

Source: Abdali K, et al. Effect of St John's wort on severity, frequency, and duration of hot flashes in premenopausal, perimenopausal and postmenopausal women. Menopause 2010;17:326-331.

Estrogen levels decline in premenopausal, perimenopausal, and postmenopausal women, causing vasomotor symptoms. The objective of this study was to assess the effects of SJW on hot flashes. One hundred women from an academic health center in Iran were recruited to participate in this study. Subjects were randomized to receive either SJW or placebo for 8 weeks. The trial interventions were drops containing either placebo or SJW extract (Hypiran, Poursina Pharmaceutical Mfg Co., Tehran, Iran). The SJW drops contained hypericin 0.2 mg/mL, and placebo was distilled water; the drops were identical in smell, color, and taste. Subjects were advised to take 20 drops of the medicine, three times per day, for 2 months. Blatt-Kupperman Index, a validated scoring of menopausal symptoms, was the primary outcome variable. Average age of the subjects was 50.4 years. Both groups improved over time, and the difference from baseline for each group was statistically significant. The difference between the groups in the duration of hot flashes was not different at 4 weeks, but it was improved at 8 weeks in the treatment group compared to the placebo group. Both severity and frequency of hot flashes were improved at both 4 and 8 weeks in the treatment group compared to the placebo group.

Commentary

The design and methodology of this study are excellent; it is randomized, double-blind, and placebo-controlled. Intention-to-treat was used as the primary analysis. Loss to follow-up was minimal, and a power analysis was presented. The method of randomization is described; a random table was used, but allocation concealment was not described.

Within this excellent design, however, some limitations are noted. The study enrolls premenopausal, perimenopausal, and postmenopausal women with hot flashes; definitions are given for each group, and the age range of the subjects was 45-55 years. This age range is appropriate, but one may question if they were able to differentiate between premenopausal and perimenopausal women based on their definitions. Interestingly, the conclusion given by the authors is that SJW can be used as an effective treatment for the vasomotor symptoms of perimenopausal or postmenopausal women. No mention of premenopausal women is noted in the conclusion, but the text does not describe differences in effectiveness between the menopause categories.

Another limitation is that the eligibility criteria are confusing. For instance, women were included if they were having untreated complaints for at least 2 months, but excluded if they had had any treatment to alleviate climacteric symptoms in the last 12 weeks before study entry. Two different eligibility criteria describe the frequency of hot flashes: One criterion is that they must be experiencing moderate-to-severe hot flashes at least once per day, and a different eligibility criterion is that they must be having three or more hot flashes per day. One would assume that the population must be having three or more hot flashes per day, with at least one of these being severe.

Compared with other hot flash studies, the frequency and severity of the hot flashes are rather small, and one might question whether the ceiling effect may play a role. If the subject is only having three hot flashes per day, with two of those being mild, how much better can she get? Justification for these eligibility criteria is not stated.

Lastly, smoking, drinking alcohol, and drinking caffeine excluded participation in this study; generalizability may come into question based on these exclusion criteria. Overall, the study population, design, methods, and analysis are appropriate.

The treatment intervention is appropriate, but likely not for the reasons that the authors state. The authors repeatedly note that SJW is a phytoestrogen, and that the phytoestrogenic activity may be the mechanism of improving menopausal symptoms caused by "a decline in estradiol levels." The references in the paper that indicate that St. John's wort is a phytoestrogen are both textbook references, not original research. It is unlikely that original research demonstrating that the mechanism of action of St. John's wort is phytoestrogenic activity would be presented first in a textbook. The Natural Medicines Comprehensive Database does not list phytoestrogenic or sex hormone effects as a mechanism of action for St. John's wort.1

St. John's wort is best known for its effects on mild-to-moderate depression,2 and it likely has serotonergic effects, inhibiting uptake of serotonin, dopamine, and norepinephrine.1 It would make sense that a botanical that has similar pharmacologic effects to a serotonin and norepinephrine reuptake inhibitor like venlafaxine might be beneficial for vasomotor symptoms, since venlafaxine is effective for hot flashes.3 Thus, SJW might be effective both for vasomotor symptoms such as hot flashes, and for mild-to-moderate depression occurring in menopause, but the mechanism of action is not likely via sex hormone pathways.

While the purported mechanism of action may not be highly relevant in the face of positive outcomes, one statement that the authors make in the background section is concerning. The authors note that St. John's wort "contains compounds called phytoestrogens, which can be used as an alternative to estrogen in women having a contraindication to use of female sex hormones." This statement is referenced with a chapter in a nursing textbook.4 However, the safety of phytoestrogens, such as soy, in hormonally sensitive conditions such as breast cancer is unknown.5-7 The authors also note that phyto-estrogens "have molecular components that are identical in structure and function to human hormones." Thus, it would be unclear why phytoestrogens, if they are identical in structure and function to human hormones, would be able to be used if there is a contraindication to use of hormones. Because SJW is likely not a phytoestrogen, it could potentially be used in women with hormonally dependent conditions.

One must keep in mind that SJW is associated with important herb/drug interactions. It is a potent inducer of some cytochrome P450 enzymes, resulting in increased metabolism and reduced plasma concentrations of many drugs, including cyclosporine, indinavir, and amitritpyline.1 Importantly, SJW also increases the metabolism of the estrogen and progestin in oral contraceptive pills.1,8 St. John's wort is associated with breakthrough bleeding, follicle growth, and probable ovulation. Thus, women of childbearing age who are using oral contraceptives should be cautioned that St. John's wort might interfere with contraceptive effectiveness.8

In conclusion, SJW might be helpful for vasomotor symptoms in women age 45-55. Longer-term studies would be helpful to delineate the risks and benefits over the many months and years that menopausal symptoms can occur.

References

1. St. John's Wort. In: Natural Medicines Comprehensive Database. Stockton, CA; 2010.

2. Linde K, et al. St John's wort for depression — an overview and meta-analysis of randomised clinical trials. BMJ 1996;313:253-258.

3. Biglia N, et al. Evaluation of low-dose venlafaxine hydrochloride for the therapy of hot flushes in breast cancer survivors. Maturitas 2005;52:78-85.

4. Adams M, Josephson D. Herbal and Alternative Therapies In: Pharmacology for Nursing. Upper Saddle River, NJ: Pearson Prentice Hall; 2005:100-141.

5. Harris RMW, et al. Phytoestrogens are potent inhibi- tors of estrogen sulfation: Implications for breast cancer risk and treatment. J Clin Endocrinol Metab 2004;89:1779-1787.

6. Dees C, et al. Dietary estrogens stimulate human breast cells to enter the cell cycle. Environ Health Perspect 1997;105(Suppl 3):633-636.

7. deLemos M. Safety issues of soy phytoestrogens in breast cancer patients. J Clin Oncol 2002;20:3040-3041.

8. Murphy P, et al. 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;71:402-408.