Evening Primrose Oil for Menopause Hot Flashes: Systematic Review and Meta-Analysis

Abstract

Hormone replacement therapy (HRT) used to treat hot flashes has side effects, such as an increased risk of coronary heart disease and breast cancer. There are ongoing controversies regarding the risk of ovarian cancer associated with HRT. HRT is best avoided in conditions such as liver or gallbladder disease and gastrointestinal disorders. Evening primrose oil (EPO) has been used as an alternative treatment for hot flashes. We conducted a systematic review of randomized controlled trials and controlled clinical trials, following the PRISMA guidelines, to compare EPO with placebo or other interventions in alleviating hot flashes in menopausal women. We analyzed the data using Review Manager version 5.3, in conjunction with the Cochrane Collaboration tool. The severity of hot flashes was lower when EPO was administered for less than 6 months compared to placebo. However, there was no significant difference in the frequency and duration of hot flashes between EPO and placebo. Participants who received EPO complained of mild nausea and headache. EPO did not show any significant difference in the severity of hot flashes compared to black cohosh at 4 weeks; but the hot flashes were more severe at 8 weeks in the EPO group compared to black cohosh. The current evidence is insufficient to draw firm conclusions regarding the benefits of EPO in alleviating hot flashes. We hope that more research is conducted to provide sufficient evidence for menopausal women considering the use of EPO.

Graphical Abstract

INTRODUCTION

Menopause, which is cessation of menstruation is a physiological process of the female reproductive system. Decreased estrogen and progesterone production in the ovaries leads to various physiological and psychological symptoms which are not only distressing but may affect the quality of life in some as well. The vasomotor symptoms of menopause include hot flashes, sweating at night, disturbances in sleep, and mood disorders.

Interestingly, the history of menopause shows that it has had differing views even scientifically. Napheys in 1981 described it as an “unpleasant train of symptoms that can be alarming, painful, and often entailing sad consequences, though rarely fatal.” He found that physicians tended to ridicule these complaints [1]. In 1965, physicians recognized menopause and endocrine changes which lead to the use of hormone replacement therapy (HRT) [2]. Several cohort studies conducted show the various menopausal changes seen in the biological and psychological changes in the lifecycle of women.

Hot flashes are a classic symptom of menopause and 90% of patients seek treatment for it [3]. Some studies show that 30% to 70% of premenopausal women experience hot flashes [4] while other studies show that 85% experience vasomotor symptoms cumulatively [5]. Hot flashes can occur at any time of the night or day spontaneously or triggered by temperature, alcohol, stress, or caffeine. It is experienced as intense heat or warmth followed by sweating and skin reddening, and it may be accompanied by palpitations. The duration can vary from 3 to 4 minutes to about an hour [6,7].

Both hormonal and non-hormonal therapy such as complementary therapy, lifestyle changes, and other alternatives have been used in the treatment of hot flashes.

HRT has been used over many decades but they are not without complications. Randomized trials have not only shown no benefit in HRT for menopause but also shown that there is an increased risk of coronary heart disease (CHD) and breast cancer [8,9,10]. There are controversies about the risk of HRT and ovarian cancer about whether the risk is small [11] or not significant [12,13]. Reanalysis of observational and randomized studies with stratification for age showed the benefits of HRT in women when used immediately after menopause reduce CHD and mortality [14]. These studies also found a reduction in orthopaedic fractures and various menopause symptoms [14]. In contrast, studies show that mortality and CHD increase when HRT is started more than 10 years after menopause or beyond 60 years of age [15,16,17].

Gaining weight is one of the factors why women prefer not to take HRT [18]. However, data from the Postmenopausal Estrogen/Progestin Interventions trial which is a three year multicenter double masked randomized controlled trial (RCT) do not support the fact that HRT causes weight gain [19]. Location of receiving HRT (university or private hospital), counseling by the physician, participant employment status, and knowledge about HRT constituted social factors which affected the woman’s intention to receive HRT [20]. Hickey et al. [21] advise avoiding HRT in women who have liver disease, gall stones, personal or family history of venous thromboembolism, migraine, smoking, high triglycerides and gastrointestinal absorption disorders.

Evening primrose oil (EPO, commercially) (Oenothera biennis) which is rich in omega-six fatty acids linoleic acid (60%–80%) and γ-linoleic acid (8%–14%), has been used in treating chronic inflammatory conditions such as rheumatoid arthritis and atopic dermatitis. It has also been used to relieve menopausal symptoms, premenstrual syndrome, mastalgia (breast pain) for labour induction, fibroadenomas, gestational diabetes, cervical ripening, and dilation [22,23].

EPO is prescribed as 500 mg daily for 6 weeks for menopausal hot flashes reduced hot flashes significantly compared to placebo [24]. It was assessed by the Hot Flash Related Daily Interference Scale questionnaire. The advantage of EPO is that the consumers had better social activities, sexuality, and relations with others.

It is therefore important for clinicians to understand the distress it causes and investigate sound evidence-based medicine in order to treat these symptoms in a manner that has minimal side effects and improves the quality of life of these women.

Our aim in this systematic review is to arm clinicians with the effects of EPO on alleviating hot flashes and its safety as well as the possible benefits and harms to relieve symptoms among menopausal women. Providing information despite the limitations of the current evidence is helpful to patients and can help guide them to seek the treatment option most beneficial and appealing to them.

MATERIALS AND METHODS

Types of participants

Women who have hot flashes due to peri-menopausal, menopausal, or postmenopausal stages.

Types of interventions and comparisons

We considered the studies which included oral administration of EPO of any dose, frequency, form, duration compared to placebo, or no treatment, or active compounds (herbal, hormonal therapy, nutritional preparations).

Types of outcome measures

The outcome measures included the frequency, severity, and duration of hot flashes. Moreover, the adverse effects (e.g., headache, dizziness, nausea, vomiting, and diarrhea) were also included.

Types of study designs

Two types of trials taken into account were RCT and controlled clinical (quasi-RCT).

Literature search

Using the terms-menopause, hot flashes, night sweats, EPO, we identified studies. We searched from Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library), MEDLINE, PubMed, Google Scholar, Embase, and Scopus. We also searched clinical trial registries such as ClinicalTrials.gov (www.clinicaltrials.gov/) and WHO International Clinical Trials Registry Platform (WHO ICTRP) (www.who.int/ictrp/en/). We checked the reference lists of retrieved relevant articles for additional trials.

For completion, we searched for unpublished work from abstracts of major Conferences-International Cancer Society Annual Cancer Congress meeting. Our search was till 30th September 2020.

Selection of studies, data extraction and quality assessment

We conducted the systematic review according to PRISMA systematic review template.

All authors (TT, SD, HHKS) searched, assessed the trial eligibility and screened the studies to be entered, and selected them independently. We discussed to resolve disagreements. We studied the full texts of all the articles published only in the English language. All participants consuming EPO for menopausal hot flashes were considered as participants in this research.

We assessed the biasness independently which included-random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and selective reporting (reporting bias). We graded the biasness as low, medium, or high risk.

Statistical analysis

We used Review Manager version 5.3 to analyse our data, in conjunction with the Cochrane Collaboration tool. The treatment effect of quantitative data (frequency, severity, duration of hot flashes) was calculated using the mean difference (MD) and corresponding 95% confidence intervals (CIs), while the standardised mean difference (SMD) and corresponding 95% CIs were calculated if the studies measured the same outcome using different scales. As the studies reported the outcomes (e.g., the frequency and severity of hot flashes) at the end of treatment and change from baseline, the outcomes were converted to change from baseline. We visually assessed the forest plots to determine whether there is heterogeneity. The chi² test was used and a P value of less than 0.10 was considered to demonstrate statistically significant heterogeneity. The I² statistic was used to quantify the inconsistency across the studies. The I² value was categorized as 0% to 40% as not important heterogeneity, 30% to 60% as moderate hetheterogeneity, 50% to 90% as substantial heterogeneity and 75% to 100% as considerable heterogeneity. As there was considerable heterogeneity among the included studies (I² > 50%), a random effect method was used for meta-analysis. Moreover, we performed the subgroup analysis (treatment duration less than six months vs. more than six months).

RESULTS

Although we identified 8 studies, in the end only 4 studies which met our criteria were included (Fig. 1 and Table 1) [24,25,26,27].

Fig. 1. Flow chart of selection criteria.

Table 1. Summary of studies.

Author	Study design	Aim	Subject	Intervention	Outcome
Chenoy et al. [24]	Randomized controlled trial (RCT)	Effectiveness of gamolenic acid with evening primrose oil (EPO) for hot flashes and sweating in those undergoing menopause	56 menopausal women (amenorrhea for at least 6 months) aged 45 to 67 years suffering hot flashes at least three times a day	Four capsules twice a day of 500 mg EPO with 10 mg natural vitamin E or 500 mg liquid paraffin for 6 months	Frequency and severity of daytime and night time hot and seating and any adverse effects
Dastenaie et al. [25]	RCT	Comparison of EPO with placebo group to improve menopause symptoms such as flushing, sleep disorders and musculo-skeletal disorders	100 postmenopausal women with menopausal symptoms in both drug and placebo groups. Mean age 54.6 ± 12.	EPO or placebo 1 gram twice a day for 1 month	Severity and frequency of menopause symptoms-night sweats and flushing
Farzaneh et al. [26]	RCT	To compare the efficacy of evening primrose with placebo in improvement of menopausal hot flashes using HFRDIS (hot flash related daily interference scale) questionnaire	56 postmenopausal women aged 45–59 years	Two capsules per day (totally 90 capsules for 6 weeks) of placebo or evening primrose (500 mg) for 6 weeks	Frequency and severity of hot flashes over 24-hour period and the mean duration in minutes
Mehrpooya et al. [27]	RCT	To study the effectiveness of Cimicifuga racemosa in comparison with EPO in for menopause-related symptoms	80 postmenopausal women aged 45 to 60 years with hot flashes	One group received black cohosh coated tablets and the other group received EPO capsule for 8 weeks	Severity and number of hot flashes both day and night

Risk of bias assessment

Evening primrose oil versus placebo and evening primrose oil versus black cohosh

We used Cochrane Collaboration tool to assess the risk of bias in determining the quality of the study.

Effects of interventions

Evening primrose oil versus placebo

Severity of hot flashes

The data of three trials [24,25,26] were included in the meta-analysis. The outcome was calculated as change from baseline (subtracting baseline measurement from final measurement), and SMD and its corresponding 95% CIs were calculated. In one study [25], Menopause Rating Scale was used while in another study [26], zero to ten points numeric rating scale was used. In one study [24], the scale used was not reported. The severity of hot flashes was significant lower in the EPO given less than six months compared to the placebo (SMD, –0.49; 95% CI, –0.82 to –0.16; P = 0.004). However, was no significant difference of severity of hot flashes in the EPO given for six months or more, when compared to the placebo (SMD, 0.25; 95% CI, –0.30 to 0.80; P = 0.38) (Fig. 2).

Fig. 2. Severity of hot flashes (change from baseline) between EPO versus placebo. EPO: evening primrose oil, SE: standard error, CI: confidence interval.

Frequency of hot flashes

The data of two studies [24,26] were synthesized for frequency of hot flashes per day. The outcome was calculated as change from baseline (subtracting baseline measurement from final measurement). There was no significant difference of frequency of hot flashes regardless of intervention duration between EPO and placebo (MD, 0.44; 95% CI, –1.32 to 2.20; P = 0.62). There was considerable heterogeneity among the included studies (I² = 87%).

Only one study [24] reported the frequency of night time hot flashes, and analysis showed that there was no significant difference of frequency of night time hot flashes between EPO and placebo (MD, 0.20; 95% CI, –0.63 to 1.03; P = 0.64) (Fig. 3).

Fig. 3. Frequency of daytime and nighttime hot flashes between EPO versus placebo. EPO: evening primrose oil, SD: standard deviation, CI: confidence interval.

Duration of hot flashes

Only one study [26] reported the duration of hot flashes in minutes. There was no significant difference in the duration of hot flashes between those receiving EPO compared to placebo (MD, 0.30; 95% CI, –2.39 to 2.99; P = 0.83) (Fig. 4).

Fig. 4. Duration of hot flashes (minutes) between EPO versus placebo. EPO: evening primrose oil, SD: standard deviation, CI: confidence interval.

Side effects

Among the group of participants who had received EPO, mild nausea was reported by three women in one study [24] and by two women in another study [26]. Only one woman reported headache in one study [26].

Evening primrose oil versus black cohosh

Only one study [27] was included for the comparison of EPO and black cohosh. There was no significant difference between EPO and black cohosh on the severity of hot flashes at 4 weeks after intervention (MD, 0.27; 95% CI, –0.04 to 0.58; P = 0.08), however, the women who received EPO had higher severity score compared to those who had black cohosh at 8 weeks (MD, 0.42; 95% CI, 0.17 to 0.67; P = 0.001) (Fig. 5).

Fig. 5. Severity of hot flashes between EPO versus black cohosh. EPO: evening primrose oil, SD: standard deviation, CI: confidence interval.

With regards to the frequency of hot flashes, there were no significant difference between the groups at both 4 weeks (MD, 0.14; 95% CI, –0.14 to 0.42; P = 0.32) and 8 weeks (MD, 0.17; 95% CI, –0.09 to 0.43; P = 0.21). None of the women reported side effects during the study (Fig. 6).

Fig. 6. Frequency of hot flashes between EPO versus black cohosh. EPO: evening primrose oil, SD: standard deviation, CI: confidence interval.

DISCUSSION

In this study, we found that the severity of hot flashes was lower when EPO was taken for less than 6 months but not when taken for more than 6 months when compared to placebo. There was no difference in the frequency and duration of hot flashes. However, when compared to black cohosh, the severity of hot flashes was more in EPO at 8 weeks but there was not difference in frequency.

Hot flashes which are vasomotor symptoms of menopause are best alleviated by oestrogen based therapy according to the U.S. Food and Drug Administration (FDA). Global data has found that the use of HRT has dropped year by year resulting in more detrimental effects of menopause [28]. Therefore there was a need to find alternative treatment for hot flashes. This led to using plant-derived molecules with scientific evidence to be used as a modern day treatment [29]. Tsoumani et al. [30] found using the Michigan Cancer Foundation 7 cell line that both evening primrose and black cohosh produced oestrogen.

EPO is a phytoestrogen which may act as an agonist or an antagonist of oestrogen to reduce the effects of hot flashes [31]. Similar to this study, Yousefi et al. [32] found that EPO is effective in reducing the severity of hot flashes but contrary to our study, they found a decrease in the frequency of hot flashes.

The participants reported mild nausea and headache. Other studies also found headaches and gastrointestinal upsets with EPO [22,33]. Bamford et al. [33] in their meta-analysis for Eczema found that the gastrointestinal effects were not severe enough to withdraw EPO.

CONCLUSION

There is currently insufficient evidence to conclude that EPO is beneficial to alleviate hot flashes in menopausal women. We suggest further research be done to study the effects of EPO on hot flashes so that if there is enough evidence women may use it as an alternative to HRT with fewer side effects.